8β,11β,12α-PGF2.sub.α compounds

ABSTRACT

This invention is a group of 8-β, 12-α-PG 2  (prostaglandin-type) analogs having variable chain length, or methyl or phenyl substitution in the hydroxy-substituted side-chain, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, and labor inducement at term.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 374,405, filed June 28, 1973,which is a continuation-in-part of my copending application Ser. No.289,317 filed Sept. 15, 1972, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel compositions of matter, to novel methodsfor producing those, and to novel chemical intermediates useful in thoseprocesses. Particularly, this invention relates to certain novel analogsof prostaglandins E₂ , F₂.sub.α, and F₂.sub.β in which the configurationat C-8 is beta and at C-12 is alpha, and in which there is variablechain length, or methyl or phenyl substitution in the hydroxysubstitutedside-chain.

The known prostaglandins include, for example, prostaglandin E₂ (PGE₂),prostaglandin F₂ alpha and beta (PGF₂.sub.α and PGF₂.sub.β), andprostaglandin A₂ (PGA₂). Each of the above-mentioned knownprostaglandins is a derivative of prostanoic acid which has thefollowing structure and atom numbering: ##STR1## See, for example,Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references citedtherein. A systematic name for prostanoic acid is7-([2β-octyl]-cyclopent-1β-yl]- heptanoic acid.

PGE₂ has the following structure: ##STR2##

PGF₂.sub.α has the following structure: ##STR3##

PGF₂.sub.β has the following structure: ##STR4##

PGA₂ has the following structure: ##STR5##

In formulas II to V, as well as in the formulas given hereinafter,broken line attachments to the cyclopentane ring indicate substituentsin alpha configuration, i.e., below the plane of the cyclopentane ring.Heavy solid line attachments to the cyclopentane ring indicatesubstituents in beta configuration, i.e., above the plane of thecyclopentane ring.

The side-chain hydroxy at C-15 in formulas II to V is in alpha (S)configuration. See Nature, 212, 38 (1966) for discussion of thestereochemistry of the prostaglandins.

Molecules of the known prostaglandins each have several centers ofasymmetry, and can exist in racemic (optically inactive) form and ineither of the two enantiomeric (optically active) forms, i.e. thedextrorotatory and levorotatory forms. As drawn, formulas II to V eachrepresent the particular optically active form of the prostaglandinwhich is obtained from certain mammalian tissues, for example, sheepvesicular glands, swine lung, or human seminal plasma, or by carbonyland/or double bond reduction of that prostaglandin. See, for example,Bergstrom et al., cited above. For convenience hereinafter, use of theterms PGE₂, PGF₂.sub.α, and the like, will mean the optically activeform of that prostaglandin with the same absolute configuration as PGE₂obtained from mammalian tissues.

PGE₂, PGF₂.sub.α, PGF₂.sub.β, and PGA₂, and their esters, acylates, andpharmacologically acceptable salts, are extremely potent in causingvarious biological responses. For that reason, these compounds areuseful for pharmacological purposes. See, for example, Bergstrom et al.,cited above. A few of those biological responses are stimulation ofsmooth muscle as shown, for example, by tests on strips of guinea pigileum, rabbit duodenum, or gerbil colon; potentiation or other smoothmuscle stimulants; antilipolytic activity as shown by antagonism ofepinephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion in the case of the PGE and PGA compoundsas shown in dogs with secretion stimulated by food or histamineinfusion; activity on the central nervous system; controlling spasm andfacilitating breathing in asthmatic conditions; decrease of bloodplatelet adhesiveness as shown by platelet-to-glass adhesiveness, andinhibition of blood platelet aggregation and thrombus formation inducedby various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen;and in the case of the PGE and PGB compounds, stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 μg. to about10 mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE, PGF.sub.α, PGF.sub.β, and PGA compounds are useful in thetreatment of asthma. For example, these compounds are useful asbronchodilators or as inhibitors of mediators, such as SRS-A, andhistamine which are released from cells activated by an antigen-antibodycomplex. Thus, these compounds control spasm and facilitate breating inconditions such as bronchial asthma, bronchitis, bronchiectasis,pneumonia and emphysema. For these purposes, these compounds areadministered in a variety of dosage forms, e.g., orally in the form oftablets, capsules, or liquids; rectally in the form of suppositories;parenterally, subcutaneously, or intramuscularly, with intravenousadministration being preferred in emergency situations; by inhalation inthe form of aerosols or solutions for nebulizers; or by insufflation inthe form of powder. Doses in the range of about 0.01 to 5 mg. per kg. ofbody weight are used 1 to 4 times a day, the exact dose depending on theage, weight, and condition of the patient and on the frequency and routeof administration. For the above use these prostaglandins can becombined advantageously with other anti-asthmatic agents, such assympathomimetics (isoproterenol, phenylephrine, ephedrine, etc);xanthine derivatives (theophylline and aminophyllin); andcorticosteroids (ACTH and prednisolone). Regarding use of thesecompounds see South African Pat. No. 68/1055.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 μg. to about 500 μg.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about 20 mg. per kg. of bodyweight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful whenever it isdesired to inhibit platelet aggregation, to reduce the adhesivecharacter of platelets, and to remove or prevent the formation ofthrombi in mammals, including man, rabbits, and rats. For example, thesecompounds are useful in the treatment and prevention of myocardialinfarcts, to treat and prevent post-operative thrombosis, to promotepatency of vascular grafts following surgery, and to treat conditionssuch as atherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situation, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGF.sub.α, and PGF.sub.β compounds are especially useful asadditives to blood, blood products, blood substitutes, and other fluidswhich are used in artifical extracorporeal circulation and perfusion ofisolated body portions, e.g., limbs and organs, whether attached to theoriginal body, detached and being preserved or prepared for transplant,or attached to the new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE₂, for example, is useful in place of or in combinationwith less than usual amounts of these known smooth muscle stimulators,for example, to relieve the symptoms of paralytic ileus, or to controlor prevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 μg. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especially in cases of severelyimpaired renal blood flow, for example, the hepatorenal syndrome andearly kidney transplant rejection. In cases of excessive orinappropriate ADH (antidiuretic hormone; vasopressin) secretion, thediuretic effect of these compounds is even greater. In anephric states,the vasopressin action of these compounds is especially useful.Illustratively, the PGA compounds are useful to alleviate and correctcases of edema resulting, for example, from massive surface burns, andin the management of shock. For these purposes, the PGA compounds arepreferably first administered by intravenous injection at a dose in therange 10 to 1000 μg. per kg. of body weight or by intravenous infusionat a dose in the range 0.1 to 20 μg. per kg. of body weight per minuteuntil the desired effect is obtained. Subsequent doses are given byintravenous, intramuscular, or subcutaneous injection or infusion in therange 0.05 to 2 mg. per kg. of body weight per day.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful in place ofoxytocin to induce labor in pregnant female animals, including man,cows, sheep, and pigs, at or near term, or in pregnant animals withintrauterine death of the fetus from about 20 weeks to term. For thispurpose, the compound is infused intravenously at a dose of 0.01 to 50μg. per kg. of body weight per minute until or near the termination ofthe second stage of labor, i.e., expulsion of the fetus. These compoundsare especially useful when the female is one or more weeks post-matureand natural labor has not started, or 12 to 60 hours after the membraneshave ruptured and natural labor has not yet started. An alternativeroute of administration is oral.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful for controllingthe reproductive cycle in ovulating female mammals, including humans andanimals such as monkeys, rats, rabbits, dogs, cattle, and the like. Bythe term ovulating female mammals is meant animals which are matureenough to ovulate but not so old that regular ovulation has ceased. Forthat purpose, PGF₂.sub.α, for example, is administered systemically at adose level in the range 0.01 mg. to about 20 mg. per kg. of body weightof the female mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Intravaginal and intrauterineare alternative routes of administration. Additionally, expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the normal mammalian gestationperiod.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGE compounds promote and accelerate the growth of epidermal cellsand keratin in animals, including humans, useful domestic animals, pets,zoological specimens, and laboratory animals. For that reason, thesecompounds are useful to promote and accelerate healing of skin which hasbeen damaged, for example, by burns, wounds, and abrasions, and aftersurgery. These compounds are also useful to promote and accelerateadherence and growth of skin autografts, especially small, deep (Davis)grafts which are intended to cover skinless areas by subsequent outwardgrowth rather than initially, and to retard rejection of homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject.Especially for topical use, these prostaglandins are useful incombination with antibiotics, for example, gentamycin, neomycin,polymyxin B, bacitracin, spectinomycin, and oxytetracyline, with otherantibacterials, for example, mafenide hydrochloride, sulfadiazine,furazolium chloride, and nitrofurazone, and with corticoid steroids, forexample, hydrocortisone, prednisolone, methylprednisolone, andfluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel 8-beta,12-alpha-prostaglandin E₂ and F₂ analogs. It is a further purpose toprovide such analogs having variable chain length, or methyl or phenylsubstitution in the hydroxy-substituted side-chain. ##STR6##

There are also included the alkanoates of 2 to 8 carbon atoms inclusive,and the pharmacologically acceptable salts derived from these compoundswhen R₁₃ is hydrogen.

In formulas VI to XIV, inclusive, R₄, R₅, and R₇ are hydrogen or methyl,being the same or different, R₆ is n-butyl or ##STR7## wherein s iszero, one, 2, or 3; R₁₃ is hydrogen, alkyl of one to 12 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one,2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive; and R₂₁ ishydrogen or alkyl of one to 5 carbon atoms, inclusive.

Formulas VI to XIV represent 8-beta, 12-alpha-prostaglandin E and F typecompounds, i.e. analogs of PGE₂, PGF₂.sub.α and PGF₂.sub.α in which theconfiguration at C-8 is beta rather than alpha as in the naturalprostaglandins, and at C-12 is alpha rather than beta. For example,formula VI represents 8β,12α-PGE₂ when R₄, R₅, R₇, and R₁₃ are hydrogen,and R₆ is n-butyl.

Formulas IX to XI represent analogs wherein the hydroxyl at C-11 is inbeta configuration rather than in the alpha configuration of the naturalprostaglandins. For example, formula X represents 8β,9α,11β,12α-PGF₂,methyl ester, (alternately 8β,11β,12α-PGF₂ α, methyl ester) when R₄, R₅,and R₇ are hydrogen, R₆ is n-butyl, and R₁₃ is methyl.

Formulas XII to XIV represent analogs wherein --OR₂₁ at C-15 is in betaconfiguration rather than in the alpha configuration of the naturalprostaglandins. For example, formula XIV represents 8β,9β,15β-PGF₂ whenR₄, R₅, R₇, R₁₃, and R₂₁ are hydrogen, and R₆ is n-butyl.

In formulas VI to XIV, when R₆ is ##STR8## the chain length of thehydroxy-substituted side-chain is 5 carbon atoms plus the terminalphenyl group. For example, Formula VI represents17-phenyl-18,19,20-trinor-8β,12α-PGE₂ when R₄, R₅, R₇, and R₁₃ arehydrogen, and R₆ is ##STR9## wherein s is zero, i.e. benzyl. In the nameof this formula-VI example, "18,19,20-trinor" indicates absence of threecarbon atoms from the hydroxy-substituted side-chain of the PGE₂structure. Following the atom numbering of the prostanoic acidstructure, C-18, C-19, and C-20 are construed as missing. The phenylsubstitution on C-17, therefore, terminates the side chain.

In formulas VI to XIV, when R₇ is methyl, each formula represents a15-methyl prostaglandin analog. For example, formula VII represents15-methyl-8β,9α,12α-PGF₂ when R₄, R₅, and R₁₃ are hydrogen, R₆ isn-butyl, and R₇ is methyl.

In formulas VI to XIV, when one or both of R₄ and R₅ are methyl, aformula represents either 16-methyl or 16,16-dimethyl substitution. Forexample, formula VIII represents 16-methyl-8β,9β,12α-PGF₂ when R₄ ismethyl, R₅, R₇, and R₁₃ are hydrogen, and R₆ is n-butyl; formula IXrepresents 16,16-dimethyl-8β,11β,12α-PGE₂, methyl ester, when R₄, R₅,and R₁₃ are methyl, R₆ is n-butyl, and R₇ is hydrogen.

With regard to formulas VI to XIV, examples of alkyl of one to 12 carbonatoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and isomeric formsthereof. Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive,which includes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkylof 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl,1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl,2-(1-naphthylethyl), and 1-(2-naphthylmethyl). Examples of phenylsubstituted by one to 3 chloro or alkyl of one to 4 carbon atoms,inclusive, are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, and4-chloro-2-methylphenyl.

Accordingly, there is provided an optically active compound of theformula ##STR10## wherein R₄, R₅, and R₇ are hydrogen or methyl, beingthe same or different; wherein R₆ is n-butyl or ##STR11## wherein s iszero, one, 2, or 3; wherein R₁₃ is hydrogen, alkyl of one to 12 carbonatoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkylof 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted withone, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive; R₂₁ ishydrogen or alkyl of one to 5 carbon atoms, inclusive; and wherein W is##STR12## including the lower alkanoates thereof, and thepharmacologically acceptable salts thereof when R₁₃ is hydrogen.

Formula XV represents PGE₂ analogs when W is ##STR13## PGF₂.sub.αanalogs when W is ##STR14## and PGF₂.sub.β analogs when W is ##STR15##

There is also provided an optically active compound of the formula##STR16## wherein R₄, R₅, R₆, R₇, R₁₃, R₂₁, and W are as defined above.

There is further provided an optically active compound of the formula##STR17## wherein R₄, R₅, R₆, R₇, R₁₃, R₂₁, and W are as defined above,representing the C-11 epimers of formula-XV compounds.

The novel formula VI-to-XVII compounds of this invention each cause thebiological responses described above for the PGE, PGF.sub.α, PGF.sub.β,and PGA compounds, respectively, and each of these novel compounds isaccordingly useful for the above-described corresponding purposes, andis used for those purposes in the same manner as described above.

The known PGE, PGF.sub.α, PGF.sub.β, and PGA compounds are all potent incausing multiple biological responses even at low doses. For example,PGE₂ causes vasodepression and smooth muscle stimulation at the sametime it exerts antilipolytic activity. Moreover, for many applications,these known prostaglandins have an inconveniently short duration ofbiological activity. In striking contrast, the novel prostaglandinanalogs of formulas VI to XVII are substantially more specific withregard to potency in causing prostaglandin-like biological responses,and have a substantially longer duration of biological activity.Therefore, each of these novel prostaglandin analogs is surprisingly andunexpectedly more useful than one of the corresponding above-mentionedknown prostaglandins for at least one of the pharmacological purposesindicated above for the latter, because it has a different and narrowerspectrum of biological potency than the known prostaglandin, andtherefore is more specific in its activity and causes smaller and fewerundesired side effects than when the known prostaglandin is used for thesame purpose. Moreover, because of its prolonged activity, fewer andsmaller doses of the novel prostaglandin analog can frequently be usedto attain the desired result.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope offormulas VI to XVII are preferred. For example, it is preferred that thehydroxyl at C-15 be in the alpha configuration. It is also preferredthat the hydroxyl at C-11 be in the alpha configuration. Anotherpreference is that when R₇ is methyl, R₄ and R₅ are hydrogen. Stillanother preference is that when R₆ is ##STR18## and s is not zero, atleast one chloro is in the para position to the methylene attachment tothe ring.

Another advantage of the novel compounds of this invention, especiallythe preferred compounds defined hereinabove, compared with the knownprostaglandins, is that these novel compounds are administeredeffectively orally, sublingually, intravaginally, buccally, or rectally,in addition to usual intravenous, intramuscular, or subcutaneousinjection or infusion methods indicated above for the uses of the knownprostaglandins. These qualities are advantageous because they facilitatemaintaining uniform levels of these compounds in the body with fewer,shorter, or smaller doses, and make possible self-administration by thepatient.

The 8β,12α prostaglandin E and F analogs encompassed by formulas VI toXVII including their alkanoates, are used for the purposes describedabove in the free acid form, in ester form, or in pharmacologicallyacceptable salt form. When the ester form is used, the ester is any ofthose within the above definition of R₁₃. However, it is preferred thatthe ester be alkyl of one to 12 carbon atoms, inclusive. Of those alkyl,methyl and ethyl are especially preferred for optimum absorption of thecompound by the body or experimental animal system; and straight-chainoctyl, nonyl, decyl, undecyl, and dodecyl are especially preferred forprolonged activity in the body or experimental animal.

Pharmacologically acceptable salts of these formula VI-to-XVII compoundsuseful for the purposes described above are those with pharmacologicallyacceptable metal cations, ammonium, amine cations, or quaternaryammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine,2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and thelike, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine,N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

The compounds encompassed by formulas VI to XVII are used for thepurposes described above in free hydroxy form or also in the formwherein the hydroxy moieties are transformed to lower alkanoatemoieties, e.g., --OH to --OCOCH₃. Examples of lower alkanoate moietiesare acetoxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy,heptanoyloxy, octanoyloxy, and branched chain alkanoyloxy isomers ofthose moieties. Especially preferred among these alkanoates for theabove described purposes are the acetoxy compounds. These free hydroxyand alkanoyloxy compounds are used as free acids, as esters, and in saltform all as described above.

As discussed above, the compounds of formulas VI to XVII areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action. For intravenous injection or infusion, sterileaqueous isotonic solutions are preferred. For that purpose, it ispreferred because of increased water solubility that R₁₃ in the formulaVI-to-XVII compound be hydrogen or a pharmacologically acceptablecation. For subcutaneous or intramuscular injection, sterile solutionsor suspensions of the acid, salt, or ester form in aqueous ornon-aqueous media are used. Tablets, capsules, and liquid preparationssuch as syrups, elixirs, and simple solutions, with the usualpharmaceutical carriers, are used for oral sublingual administration.For rectal or vaginal administration, suppositories prepared as known inthe art are used. For tissue implants, a sterile tablet or siliconerubber capsule or other object containing or impregnated with thesubstance is used.

The 8β,12α-prostaglandin E₂ and F₂ analogs encompassed by formulas VIthrough XVII are produced by the reactions and procedures described andexemplified hereinafter.

Reference to Charts A, B, C, and D herein will make clear the processsteps. In Chart A is shown the transformation of the starting materialcontaining an anion of the formula ##STR19##

                  CHART A                                                         ______________________________________                                         ##STR20##                                                                     ##STR21##                                                                     ##STR22##                                                                     ##STR23##                                                                     ##STR24##                                                                     ##STR25##                                                                     ##STR26##                                                                     ##STR27##                                                                     ##STR28##                                                                     ##STR29##                                                                    ______________________________________                                    

wherein R₁ is methyl or benzyl to a key intermediate ##STR30## whereinM' is ##STR31## wherein R₈ is hydrogen or a blocking group Z, as definedhereinafter, and wherein Q is ##STR32## wherein R₄, R₅, and R₆ are asdefined above. The starting material is readily available. See E. J.Corey et al., J. Am. Chem. Soc. 92, 397 (1970) describing the resolutionof XVIII with (-)-ephedrine.

Iodolactone XIX is obtained by methods known in the art, e.g. treatmentof the sodium salt of XVIII in water with potassium triiodide. Theformula-XX compound is obtained by deiodination of XIX using a reagentwhich does not react with the lactone ring, e.g. zinc dust, sodiumhydride, hydrogen-palladium, hydrogen and Raney nickel or platinum, andthe like. Especially preferred is tributyltin hydride in benzene atabout 5° C. with 2,2'-azobis-(2-methylpropionitrile) as initiator.

Compound XXI is obtained by reacting the formula-XX compound with ahydrocarbonsulfonyl or halohydrocarbonsulfonyl chloride or bromide,preferably a lower alkanesulfonyl chloride or bromide, especiallymethanesulfonyl chloride, or a benzene- or substituted- benzenesulfonylchloride or bromide, e.g. 2-bromobenzenesulfonyl chloride orp-toluenesulfonyl chloride. This reaction is done in the presence of asufficient amount of tertiary amine, e.g. triethylamine or pyridine, toabsorb the hydrogen chloride or hydrogen bromide by-product, and at alow temperature, preferably not over 30° C.

Inversion from beta configuration at the 3-position of the formula-XXIlactone to the alpha configuration at the 3-position of the formula-XXIIlactone is achieved by reaction of the formula-XXI sulfonate with analkali metal salt of an aliphatic acid, preferably lower aliphatic ofone to 8 carbon atoms, especially acetic acid, or an aromatic acid,including benzoic, substituted benzoic, monoesterified phthalic or itsisomers, naphthoic, and substituted naphthoic. This reaction is done inan organic liquid medium such as dimethyl sulfoxide in the range of50°-100° C. At about 85° C. the reaction is complete in 3-4 hours,resulting in inversion and replacement at the 3-position of thesulfonate moiety by R₃, defined herein as ##STR33## wherein T is alkylof one to 4 carbon atoms, inclusive, phenylalkyl of 7 to 10 carbonatoms, inclusive, or nitro, and s is zero to 5, inclusive, provided thatnot more than two T's are other than alkyl, and that the total number ofcarbon atoms in the T's does not exceed 10 carbon atoms; ##STR34##wherein R₁₄ is alkyl of one to 4 carbon atoms inclusive; ##STR35##wherein T and s are as defined above; or (d) acetyl.

Examples of R₃ are benzoyl, substituted benzoyl, e.g. (2-, 3- or4-)methylbenzoyl, (2-, 3-, or 4-)ethylbenzoyl, (2-, 3-, or4-)isopropylbenzoyl, (2-, 3-, or 4-)tert-butylbenzoyl,2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl,2,4,6-trimethylbenzoyl, pentamethylbenzoyl, α-phenyl-(2-, 3-, or4-)toluyl, 2-, 3-, or 4-phenethylbenzoyl, 2-, 3-, or 4-nitrobenzoyl,(2,4-, 2,5-, or 3,5-)dinitrobenzoyl, 3,4-dimethyl-2-nitrobenzoyl,4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenethylbenzoyl,3-nitro-2-phenethylbenzoyl; mono-esterified phthaloyl, e.g. ##STR36##isophthaloyl, e.g. ##STR37## or terephthaloyl, e.g. ##STR38## (1- or2-)naphthoyl; and substituted naphthoyl, e.g. (2-, 3-, 4-, 5-, 6-, or7-)methyl-1-naphthoyl, (2- or 4-)ethyl-1-naphthoyl,2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl,6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5- or8-)nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7- or8-)methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or8-)nitro-2-naphthoyl.

The formula-XXIII compound is obtained by demethylation (ordebenzylation) of XXII with a reagent that does not attack the OR₃moiety, for example, boron tribromide or trichloride. The reaction iscarried out preferably in an inert solvent at about 0°-5° C.

The formula-XXIV compound is obtained by oxidation of the --CH₂ OH ofXXIII to --CHO, avoiding decomposition of the lactone ring. Useful forthis purpose are dichromatesulfuric acid, Jones' reagent, or leadtetraacetate. Especially preferred is Collins' reagent (pyridine-C_(r)O₃) at about 0°-10° C.

The formula-XXV compound is obtained by Wittig alkylation of XXIV, usinga ylide consisting of a phosphonate anion of the formula ##STR39##wherein R₁₅ is alkyl of one to 8 carbon atoms, inclusive, and R₄, R₅,and R₆ are as defined above. The trans enone lactone is obtainedstereospecifically (see D. H. Wadsworth et al., J. Org. Chem. 30, 680(1965)).

The phosphonates are available or prepared by methods known in the art,e.g. by reaction of a dialkyl methylphosphonate with an ethyl ester ofan appropriate aliphatic acid or phenyl-substituted aliphatic acid.

The formula-XXVI compound, wherein M is ##STR40## wherein R₇ is hydrogenand wherein Q is as defined above, is obtained as a mixture of the alphaand beta isomers with respect to M, by reduction of XXV. For thisreduction, use is made of any of the known ketonic carbonyl reducingagents which do not reduce ester or acid groups or carbon-carbon doublebonds when the latter is undesirable. Examples of those are the metalborohydrides, especially sodium, potassium, and zinc borohydrides,lithium (tri-tert-butoxy) aluminum hydride, metal trialkoxyborohydrides, e.g., sodium trimethoxyborohydride, lithium borohydride,diisobutyl aluminum hydride. The alpha and beta isomers are separated bychromatography, e.g. silica gel chromatography or high pressure liquidchromatography. See, for example, "Modern Practice of LiquidChromatography", J. J. Kirkland, ed., Wiley-Interscience, 1971.

The formula-XXVII compound is obtained, if desired, by deacylation ofXXVI with an alkali metal carbonate, for example potassium carbonate inmethanol at about 25° C. Thereafter, compound XXVII may be used directlyin the steps shown in Chart B, in which case XXVII is identical withXXVIII.

                  CHART B                                                         ______________________________________                                         ##STR41##                                                                     ##STR42##                                                                     ##STR43##                                                                     ##STR44##                                                                     ##STR45##                                                                     ##STR46##                                                                    ______________________________________                                    

Alternately, compound XXVIII of Charts A and B is made by replacinghydrogen atoms on all hydroxyls with a blocking group Z.

The blocking group, Z, is any group which replaces hydrogen of thehydroxyl groups, which is not attacked by nor is reactive to thereagents used in the respective transformations to the extent that thehydroxyl group is, and which is subsequently replaceable by hydrogen ata later stage in the preparation of the prostaglandin-like products.

Several blocking groups are known in the art, e.g. tetrahydropyranyl,acetyl, and p-phenylbenzoyl (see Corey et al., J. Am. Chem. Soc. 93,1491 (1971)).

Those which have been found useful include (a) carboxyacyl within thescope of R₃, defined above, i.e. acetyl, benzoyl, naphthoyl, and thelike; (b) tetrahydropyranyl; (c) tetrahydrofuranyl; (d) a group of theformula ##STR47## wherein R₁₆ is alkyl of one to 18 carbon atoms,inclusive, cycloalkyl of 3 to 10 atoms, inclusive, aralkyl of 7 to 12carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3alkyl of one to 4 carbon atoms, inclusive, wherein R₁₇ and R₁₈ are thesame or different, being hydrogen, alkyl of one to 4 carbon atoms,inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of oneto 4 carbon atoms, inclusive, or, when R₁₇ and R₁₈ are taken together,--(CH₂)a-- or --(CH₂)b-- O-- (CH₂)c-- wherein a is 3, 4, or 5, b is one,2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3,or 4, and wherein R₁₉ is hydrogen or phenyl; or (e) --Si(A)₃ wherein Ais alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substitutedwith one or 2 fluoro, chloro, or alkyl of one to 4 carbon atoms,inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive.

It is desirable that the formula-XXVIII intermediate have a blockinggroup Z at R₈, although this is not essential. It is preferred, however,that intermediate XXXII (Chart B) have a blocking group at R₉, and forthis purpose R₉ includes the blocking groups of R₈ but without thecarboxyacyl groups. It is evident, therefore, that If intermediate XXXIIis to be made, it is advantageous to prepare XXVIII with either theether-linked blocking group of types (b), (c) or (d) above, or the silylof type (e).

In replacing the hydrogen atoms of the hydroxyl groups with acarboxyacyl blocking group, methods known in the art are used. Thus, forexample, benzoic anhydride is reacted with the formula-XXVII compound inthe presence of pyridine.

Preferably, however, an acyl halide, for example, benzoyl chloride, isreacted with the formula-XXVII compound in the presence of a tertiaryamine such as pyridine, triethylamine, and the like. The reaction iscarried out under a variety of conditions using procedures generallyknown in the art. Generally, mild conditions are employed, e.g. 20°-60°C., contacting the reactants in a liquid medium, e.g. excess pyridine oran inert solvent such as benzene, toluene, or chloroform. The acylatingagent is used either in stoichiometric amount or in excess. If the acylchloride is not available, it is made from the corresponding acid andphosphorus pentachloride as is known in the art.

When the blocking group is tetrahydropyranyl or tetrahydrofuranyl, theappropriate reagent, e.g. 2,3-dihydropyran or 2,3-dihydrofuran, is usedin an inert solvent such as dichloromethane, in the presence of an acidcondensing agent such as p-toluenesulfonic acid or pyridinehydrochloride. The reagent is used in slight excess, preferably 1.0 to1.2 times theory. The reaction is carried out at about 20°-50° C.

When the blocking group is of the formula ##STR48## as defined above,the appropriate reagent is a vinyl ether, e.g. isobutyl vinyl ether orany vinyl of the formula R₁₆ -O-ClR.sub. 17)=CR₁₈ R₁₉ wherein R₁₆, R₁₇,R₁₈, and R₁₉ are defined above; or an unsaturated cyclic or heterocycliccompound, e.g. 1-cyclohex-1-yl methyl ether ##STR49## or5,6-dihydro-4-methoxy-2H-pyran ##STR50## See C. B. Reese et al., J. Am.Chem. Soc. 89, 3366 (1967). The reaction conditions for such vinylethers and unsaturates are similar to those for dihydropyran above.

When the blocking group is silyl of the formula --Si(A)₃, theformula-XXVII compound is transformed to a silyl derivative of formulaXXVIII by procedures known in the art. See, for example, Pierce,"Silylation of Organic Compounds," Pierce Chemical Co., Rockford, Ill.(1968). The necessary silylating agents for these transformations areknown in the art or are prepared by methods known in the art. See, forexample, Post "Silicones and Other Organic Silicone Compounds," ReinholdPublishing Corp., New York, N.Y. (1949). These reagents are used in thepresence of a tertiary base such as pyridine at temperatures in therange of about 0° to +50° C. Examples of trisubstituted mono-chlorosilanes suitable for this purpose include chlorotrimethylsilane,chlorotriisobutylsilane, chlorotriphenylsilane,chlorotris(p-chlorophenyl)silane, chlorotrim-tolylsilane, andtribenzylchlorosilane. Alternately, a chlorosilane is used with acorresponding disilazane. Examples of other silylating agents suitablefor forming the formula-XXVIII intermediates includepentamethylsilylamine, pentaethylsilylamine,N-trimethylsilyldiethylamine, 1,1,1-triethyl-N,N-dimethylsilylamine,N,N-diisopropyl-1,1,1-trimethylsilylamine,1,1,1-tributyl-N,N-dimethylsilylamine,N,N-dibutyl-1,1,1-trimethylsilylamine,1-isobutyl-N,N,1,1-tetramethylsilylamine,N-benzyl-N-ethyl-1,1,1-trimethylsilylamine,N,N,1,1-tetramethyl-1-phenylsilylamine,N,N-diethyl-1,1-dimethyl-1-phenylsilylamine,N,N-diethyl-1-methyl-1,1-diphenylsilylamine,N,N-dibutyl-1,1,1-triphenylsilylamine, and1-methyl-N,N,1,1-tetraphenylsilylamine.

Continuing with Chart B, there are shown the steps by which intermediateXXVIII is transformed to PGE analogs of formula XXXIV and to PGF analogsof formulas XXXI and XXXV. In Chart B, M'" is ##STR51## wherein R₁₀ is(a) hydrogen; (b) tetrahydropyranyl; (c) tetrahydrofuranyl; (d) a groupof the formula ##STR52## wherein R₁₆, R₁₇, R₁₈, are R₁₉ are as definedabove; or (e) --Si(A)₃ wherein A is as defined above. Also in Chart B,R₁₁ is hydrogen, methyl, or --Si(A)₃ wherein A is as defined above; R₁₂is hydrogen or methyl; ˜ indicates attachment of hydroxyl in alpha orbeta configuration; and M, M', Q, R₈ and R₉ are as defined above.

Lactol XXIX is obtained on reduction of the formula-XXVIII lactonewithout reducing the 13,14-ethylenic group. For this purpose,diisobutylaluminum hydride is used. The reduction is preferably done at-60° to -78° C.

The formula-XXX compound is obtained from lactol XXIX by the Wittigreaction, using a Wittig reagent derived from4-carboxybutyltriphenylphosphonium bromide. HOOC--(CH₂)₄ --P(C₆ H₅)₃ Br,and sodio dimethylsulfinylcarbanide. See E. J. Corey et al., J. Am.Chem. Soc. 91, 5675 (1969). The reaction is conveniently carried out atabout 25° C. This formula-XXX compound serves as an intermediate forpreparing either the PGF₂.sub.β analog XXXI or the PGE₂ analog XXXIV.The latter may serve as an intermediate for the preparation ofPGF₂.sub.α analog XXXV, wherein ˜ is alpha.

The formula-XXXI PGF₂.sub.β -type product is obtained on hydrolysis ofany blocking groups at R₁₀, e.g. tetrahydropyranyl or silyl groups. Forthis purpose, the formula-XXX compound is contacted with methanol-HCl orwith acetic acid/water/tetrahydrofuran at 40°-55° C. Specifically forthe silyl groups, milder conditions may be employed. See Pierce, citedabove, especially p. 447 thereof. A mixture of water and sufficient of awater-miscible organic diluent to give a homogeneous hydrolysis reactionmixture represents a suitable reaction medium. Addition of a catalyticamount of an organic or inorganic acid hastens the hydrolysis. Thelength of time required for the hydrolysis is determined in part by thehydrolysis temperature. With a mixture of water and methanol at 25° C.,several hours is usually sufficient for hydrolysis. At 0° C., severaldays is usually necessary.

The formula-XXXIV PGE₂ -type product is obtained by first transformingthe formula-XXX intermediate to intermediate XXXII having a blockinggroup R₉, by one of the methods described above. When R₇ at C-15 ofcompound XXX is hydrogen, the hydrogen on the C-15 hydroxyl is alsoreplaced by a blocking group in the above reaction. When R₇ is methyl,it is immaterial whether M'" contains a free hydroxyl or a blockinggroup, since the tertiary hydroxyl at C-15 is less susceptible tooxidation than the secondary hydroxyl at C-9 in the subsequent step.When silylation is employed and R₁₂ in the formula-XXX intermediate ishydrogen, the --COOH molety thereby defined is simultaneouslytransformed to --COO--Si--(A)₃, additional silylating agent being usedfor this purpose. It is immaterial whether R₁₂ is completely silylatedor not for the purposes of Chart B, so that R₁₁ may be all or partiallyhydrogen.

Successive steps in Chart B relate to the transformation of intermediateXXXII to a PGE₂ -type product by (1) oxidizing intermediate XXXII at the9-hydroxy position by known methods, e.g. with Jones or Collins reagent,and (2) replacing the blocking groups at R₉, R₁₀, and R₁₁ with hydrogen,i.e. by hydrolysis as discussed above for removal of tetrahydropyranylor silyl groups.

The formula-XXXV PGF₂.sub.α analog wherein ˜ is alpha is made from theformula-XXXIV PGE₂ analog by reduction of the carbonyl at C-9 by methodsknown in the art. See, for example, Bergstrom et al., Arkiv Kemi 19, 563(1963), Acta. Chem. Scand. 16, 969 (1962), and British Specification No.1,097,533. Any reducing agent is used which does not react withcarbon-carbon double bonds or ester groups. Preferred reagents arelithium(tri-tert-butoxy)aluminum hydride, the metal borohydrides,especially sodium, potassium and zinc borohydrides, the metal trialkoxyborohydrides, e.g., sodium trimethoxyborohydride. The mixtures of alphaand beta hydroxy reduction products are separated into the individualalpha and beta isomers by methods known in the art for the separation ofanalogous pairs of known isomeric prostanolc acid derivatives. See, forexample, Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem.240, 457 (1965), and Green et al., J. Lipid Research 5, 117 (1964).Especially preferred as separation methods are partition chromatographicprocedures, both normal and reversed phase, preparative thin layerchromatography, and countercurrent distribution procedures.

As stated above, the C-15 epimers may be separated at the formula-XXVIstage, in which case they are subjected to the successive steps ofCharts A and B individually. They may also be separated at any laterstage in Chart A or B, or if desired, left together as a mixture.

In Charts C and D are shown the steps by which the 11β analogs of thisinvention are prepared. The reactions whereby starting material XX istransformed to intermediate XLIV are substantially as described hereinfor Charts A and B, with the exception of the C-11 isomerization ofChart A employing the sulfonate-carboxylate transformation from formulaXXI to formula XXII. This isomerization is, of course, not used wherethe products of Chart C retain the configuration of starting materialXX.

In Chart C are shown intermediates XLIV and XLV which are readilytransformed to the respective8β,9β,11β,12α-PGF₂ and 8β,11β,12α-PGE₂analogs by methods known in the art or described herein.

                  CHART C                                                         ______________________________________                                         ##STR53##                                                                     ##STR54##                                                                     ##STR55##                                                                     ##STR56##                                                                     ##STR57##                                                                     ##STR58##                                                                     ##STR59##                                                                     ##STR60##                                                                     ##STR61##                                                                     ##STR62##                                                                     ##STR63##                                                                     ##STR64##                                                                     ##STR65##                                                                    ______________________________________                                    

                  CHART D                                                         ______________________________________                                         ##STR66##                                                                     ##STR67##                                                                     ##STR68##                                                                     ##STR69##                                                                     ##STR70##                                                                    ______________________________________                                    

The chromatographic separation of the C-15 epimers of the 15-methylanalogs is readily, and in fact preferably, effected on intermediateXLIII, thereafter carrying forward the individual 15α and 15β epimersthrough the sequential steps of Charts C and D. Those C-15 epimerswherein R₇ is hydrogen are separable at the formula-XL stage or anysubsequent stage, thereafter being subjected to the successive steps ofCharts C or D individually. The separation is readily achieved bymethods described herein, for example silica gel chromatography.

In Chart C is also shown the transformation of a PGE₂ -type compound toa PGA₂ analog. For this purpose intermediate XLVI is subjected to aciddehydration, using methods known in the art. See, for example, Pike etal., Proc. Nobel Symposium II, Stockholm (1966), intersciencePublishers, New York, pp. 162-163 (1967); and British Specification1,097,533. Alkanoic acids of 2 to 6 carbon atoms, inclusive, especiallyacetic acid, are preferred acids for this acidic dehydration. Diluteaqueous solutions of mineral acids, e.g., hydrochloric acid, especiallyin the presence of a solubilizing diluent, e.g., tetrahydrofuran, arealso useful as reagents for this acidic dehydration, although thesereagents may cause partial hydrolysis of an ester reactant.

Alternately when R₇ is methyl, and preferably when R₈ is acetyl,compound XLVI is contacted with potassium acetate in solution, e.g. inmethanol. the reaction proceeds smoothly at about 20°-30° C. and issubstantially free of side reactions.

The formula-XLVII PGA₂ analogs are useful compounds not only for theirprostaglandin-like properties discussed above, but as intermediates forpreparing the 11α PG₂ analogs of this invention and the C-9 epimers ofthe PGF₂ analogs according to the steps of Chart D.

In Chart D are shown the transformations of the formula-XLVII PGA₂analog to the formula LI, LII, LIII, and LIV analogs, using methodsknown in the art. See, for example, G. L. Bundy et al., J. Am. Chem.Soc. 94, 2123 (1972). There are first formed the formula-XLVIII10,11-epoxides, using any agent known to epoxidize an α,β-unsaturatedketone without reacting with isolated carboncarbon double bonds, forexample see Steroid Reactions, Carl Djerassi, ed., Holden-Day Inc.,1963, p. 593. Especially preferred are aqueous hydrogen peroxide or anorganic tertiary hydroperoxide. See, for example, Organic Peroxides, A.V. Tobolsky et al., Interscience Publishers, N. Y., 1954. For thispurpose, the peroxide or hydroperoxide is employed in an amount of atleast one equivalent per mole of Formula-XLVII reactant in the presenceof a strong base, e.g., an alkali metal hydroxide, a metal alkoxide, ora quaternary ammonium hydroxide. For example, there is employed lithiumhydroxide, sodium hydroxide, potassium hydroxide, lithium ethoxide,lithium octyloxide, magnesium methoxide, magnesium isopropoxide,benzyltrimethylammonium hydroxide, and the like.

It is advantageous to use an inert liquid diluent in the epoxidationstep to produce a mobile homogenous reaction mixture, for example, alower alkanol, dioxane, tetrahydrofuran, dimethoxyethane,dimethylsulfoxide, or dimethylsulfone. A reaction temperature in therange -60° C. is generally preferred, especially below -10° C. At atemperature of -20° C., the epoxidation is usually complete in 3 to 6hours. It is also preferred that the reaction be carried out in anatmosphere of an inert gas, e.g., nitrogen, helium, or argon. When thereaction is complete as shown by the absence of starting material on TLCplates (5% acetone in dichloromethane), the reaction mixture isneutralized, and the epoxy product is isolated by procedures known inthe art, for example, evaporation of the diluent and extraction of theresidue with an appropriate waterimmiscible solvent, e.g., ethylacetate.

This transformation of XLVII to XLVIII usually produces a mixture offormula-XLVIII alpha and beta epoxides. Although these mixtures areseparable into the individual alpha and beta isomers, for example, bychromatography by procedures known to be useful for separating alpha andbeta epoxide mixtures, it is usually advantageous to transform theformula-XLVIII mixture of alpha and beta epoxides to the correspondingmixture of formula-XLIX 11α and 11β hydroxy compounds. The lattermixture is then readily separated into the 11α and 11β compounds, forexample by chromatography on silica gel.

Referring again to Chart D, the transformation of epoxide XLVIII tohydroxy compound XLIX is accomplished by reduction with chromium (II)salts, e.g., chromium (II) chloride or chromium (II) acetate. Thosesalts are prepared by methods known in the art, e.g., InorganicSyntheses, VIII, 125 (1966); ibid., VI, 144 (1960); ibid. III, 148(1950); ibid. I, 122 (1939); and references cited in those. Thisreduction is carried out by procedures known in the art for usingchromium (II) salts to reduce epoxides of αβ-unsaturated ketones toβ-hydroxy ketones. See, for example, Cole et al., J. Org. Chem. 19, 131(1954), and Neher et al., Helv. Chem. Acta 42, 132 (1959). In thesereactions, the absence of air and strong acids is desirable.

Amalgamated aluminum metal has also been found to be useful as areducing agent in place of chromium (II) salts for the above purpose.Amalgamated aluminum is prepared by procedures known in the art, forexample, by contacting aluminum metal in the form of foil, thin sheet,turnings, or granules with a mercury (II) salt, for example, mercuricchloride, advantageously in the presence of sufficient water to dissolvethe mercury (II) salt. Preferably, the surface of the aluminum metal isfree of oxide. That is readily accomplished by physical removal of theusual oxide layer, e.g., by abrasion or scraping, or chemically, e.g.,by etching with aqueous sodium hydroxide solution. It is only necessarythat the aluminum surface be amalgamated. The amalgamated aluminumshould be freshly prepared, and maintained in the absence of air andmoisture until used.

The reductive opening of the formula-XLVIII epoxide ring is accomplishedby contacting said epoxide with the amalgamated aluminum in the presenceof a hydroxylic solvent and sufficient inert organic liquid diluent togive a mobile and homogeneous reaction mixture with respect to thehydroxylic solvent and said epoxide. Among hydroxylic solvents, water isespecially preferred although lower alkanols, e.g., methanol andethanols are also operable.

Examples of inert organic liquid diluents are normally liquid etherssuch as diethyl ether, tetrahydrofuran, dimethoxyethane, diglyme(dimethyl ether of diethylene glycol), and the like. Especiallypreferred is tetrahydrofuran. When a water-immiscible liquid diluent isused, a mixture of water and methanol or ethanol is especially useful inthis reaction since the latter two solvents also aid in forming thedesired homogeneous reaction mixture. For example, a mixture of diethylether and water is used with sufficient methanol to give a homogeneousreaction mixture.

As a modification of the above-described process for reductive openingof the epoxide, it has been found that instead of employing aformula-XLVIII compound wherein R₂₀ is hydrogen, the reductive openingreaction proceeds more smoothly and completely if there is used,instead, an epoxide wherein R₂₀ is either methyl or a cation of analkali or alkaline earth metal or a quaternary ammonium group.

Thus, a free acid formula-XLVIII epoxide compound is treated with ahydroxide or oxide of lithium, sodium, potassium, magnesium, calcium,barium, or strontium prior to contacting with the aluminum amalgam.Optionally, the quaternary ammonium bases are used for thisneutralization, for example benzyltrimethylammonium hydroxide. By usingthe above-described salts, the reduction step proceeds smoothly withoutformation of insoluble aluminum salts which hinder the reaction.Following the reduction or hydrolysis step, the R₂₀ cations are replacedwith hydrogen by means known in the art, for example by acidificationand extraction of the acid compound into an organic phase, to form theformula-L compound.

The separate C-11 epimers of formula LI and LIII, PGE₂ analogs withinthe scope of this invention, are useful prostaglandin analogs for thepurposes discussed above. They may also be transformed to thecorresponding PGF₂ analogs of formula LII and LIV, respectively, bymethods known in the art or described herein.

The 15-alkyl ether prostaglandin-type compounds included within formulasVI to XIV are produced by the sequence of reactions illustrated inCharts, E, F, and G. In general, by these methods, the 15-alkyl ethergroup is introduced into the bicyclic lactone intermediates XXVI (ChartA) and XL (Chart C) prior to the lactol formation and Wittig reactionfor forming the carboxy side chain. Alternatively, the 15-alkyl ethercompounds are prepared by alkylation of a suitably blockedprostaglandin-type compound. See Belg. Pat. No. 783,028, Nov. 6, 1972;Netherlands Application No. 7205997, Derwent Farmdoc 74818 T.

Referring to Chart E, starting material XXVI is available by theprocesses of Chart A, discussed above. In Chart E, M, Q, R₃, R₈, R₉,R₁₀, R₁₁, and R₁₂ have the same meanings as in Charts A and B; M^(1V) isdefined as ##STR71## wherein R₇ is hydrogen or methyl and R₂₂ is alkylof one to 5 carbon atoms, inclusive.

The formula-LVI compound is prepared by alkylation of the side-chainhydroxy of the formula-XXVI compound thereby replacing hydroxy with the--OR₂₂ moiety.

                  CHART E                                                         ______________________________________                                         ##STR72##                                                                     ##STR73##                                                                     ##STR74##                                                                     ##STR75##                                                                     ##STR76##                                                                     ##STR77##                                                                     ##STR78##                                                                     ##STR79##                                                                     ##STR80##                                                                    ______________________________________                                    

                  CHART F                                                         ______________________________________                                         ##STR81##                                                                     ##STR82##                                                                     ##STR83##                                                                     ##STR84##                                                                     ##STR85##                                                                     ##STR86##                                                                     ##STR87##                                                                     ##STR88##                                                                     ##STR89##                                                                     ##STR90##                                                                    ______________________________________                                    

                  CHART G                                                         ______________________________________                                         ##STR91##                                                                     ##STR92##                                                                     ##STR93##                                                                     ##STR94##                                                                     ##STR95##                                                                     ##STR96##                                                                    ______________________________________                                    

For this purpose, diazoalkanes may be employed, preferably in thepresence of a Lewis acid, e.g. boron trifluoride etherate, aluminumchloride, or fluoboric acid. When R₂₂ is methyl, diazomethane is used.See Fieser et al., "Reagents for Organic Synthesis," John Wiley andSons, Inc., N.Y. (1967), p. 191. Other --OR₂₂ groups are formed by usingthe corresponding diazoalkane. For example diazoethane and diazobutaneyield --OC₂ H₅ and --OC₄ H₉ respectively. The reaction is carried out bymixing a solution of the diazoalkane in a suitable inert solvent,preferably ethyl ether, with the formula-XXVI compound. Generally thereaction proceeds at about 25° C. Diazoalkanes are known in the art orcan be prepared by methods known in the art. See, for example, OrganicReactions, John Wiley and Sons, Inc. N.Y. Vol. 8, pp. 389-394 (1954).

Another method for the alkylation of the side chain hydroxy is by thereaction of an alcohol in the presence of boron trifluoride etherate.Thus, methanol and boron trifluoride etherate yield the methyl etherwherein R₂₂ is methyl. The reaction is done at about 25° C. and isconveniently followed with thin layer chromatography (TLC).

Another method for the alkylation of the side-chain hydroxy is by thereaction of an alkyl halide, e.g. methyl iodide, in the presence of ametal oxide or hydroxide, e.g. barium oxide, silver oxide, or bariumhydroxide. An inert solvent may be beneficial, for example benzene ordimethylformamide. The reactants are preferably stirred together andmaintained at temperatures of 25°-75° C.

Still another method is by first converting the hydroxy to mesyloxy(i.e. methanesulfonate) or tosyloxy (i.e. toluenesulfonate) and thencetransforming the mexyloxy or tosyloxy to the --OR₂₂ moiety by reactionwith a metal alkoxide, e.g. potassium tert-butoxide. The mesylate ortosylate is prepared by reaction of the formula-XXVI intermediate witheither methanesulfonyl chloride or toluenesulfonyl chloride in pyridine.Thereafter, the mesylate or tosylate is mixed with the appropriatepotassium or sodium alkoxide in pyridine, the reaction proceedingsmoothly at about 25° C. An equivalent amount of the alkoxide based onthe mesylate is preferred to avoid side reactions. In this manner, theformula-LVI intermediate is prepared wherein R₂₂ is normal alkyl,secondary alkyl, or tertiary alkyl of one to 5 carbon atoms. The methodis especially useful for tertiary alkyl substitutions for hydrogen, e.g.where R₂ is tert-butyl or tert-pentyl.

The formula-LVII compound is then obtained by deacylation of LVI with analkali metal carbonate, for example potassium carbonate in methanol atabout 25° C.

The formula-LVIII compound is the same as the formula-LVII compound whenR₈ is hydrogen, or is obtained from the formula-LVII compound byreactions discussed above when R₈ is a blocking group, such astetrahydropyranyl, tetrahydrofuranyl, or silyl. Thereafter lactol LIX isobtained by reduction and converted to LX by a Wittig reaction.Thereafter the steps by which products LXI, LXIV, and LXV are obtainedare analogous to those described above for Chart B.

Referring to Charts F and G, there are shown the steps by which the 11βanalogs of the 15 alkyl ethers are prepared. The reactions are analogousto those shown above in Charts C and D. In Charts F and G, M^(1V) isdefined as it is in Chart E above. Starting material XL of Chart F isavailable by the processes of Chart C, discussed above. Theformula-LXXIV 15-alkyl ether PGA₂ analogs of Chart F are useful per seand as intermediates for preparing the 11α 15-alkyl ether products LXIVand LXV according to Chart G.

As discussed above, the processes of Charts A-D, inclusive, leadvariously to acids (R₁₂ is hydrogen) or to esters (R₁₂ is alkyl,cycloalkyl, aralkyl, phenyl or substituted phenyl, as defined above).When an acid has been prepared and an alkyl ester is desired,esterification is advantageously accomplished by interaction of the acidwith the appropriate diazohydrocarbon. For example, when diazomethane isused, the methyl esters are produced. Similar use of diazoethane,diazobutane, and 1-diazo-2-ethylhexane, and diazodecane, for example,gives the ethyl, butyl, and 2-ethylhexyl and decyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbons are known in the art or can be prepared by methodsknown in the art. See, for example, Organic Reactions, John Wiley andSons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxyl moiety of theacid compounds comprises transformation of the free acid to thecorresponding silver salt, followed by interaction of that salt with analkyl iodide. Examples of suitable iodides are methyl iodide, ethyliodide, butyl iodide, isobutyl iodide, tert-butyl iodide, and the like.The silver salts are prepared by conventional methods, for example, bydissolving the acid in cold dilute aqueous ammonia, evaporating theexcess ammonia at reduced pressure, and then adding the stoichiometricamount of silver nitrate.

Examples of alkyl of one to 4 carbon atoms, inclusive, are methyl,ethyl, propyl, butyl, and isomeric forms thereof. Examples ofphenylalkyl of 7 to 10 carbon atoms, inclusive, are benzyl, phenethyl,1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, and 3-phenylbutyl.Examples of phenyl substituted with one or 2 fluoro, chloro, or alkyl ofone to 4 carbon atoms, inclusive, are p-chlorophenyl, m-fluorophenyl,o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl. Examples ofaralkyl of 7 to 12 carbon atoms, inclusive, other than the phenylalkylexamples above, are α-naphthylmethyl, and 2-(β-naphthyl)ethyl.

Examples of alkyl of one to 12 carbon atoms, inclusive, are, in additionto those alkyl examples above, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, and isomeric forms thereof. Examples ofcycloalkyl of 3 to 10 carbon atoms, inclusive, which includesalkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl,2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl,cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of alkyl of one to 18 atoms, inclusive, are, in addition tothose alkyl examples above, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl, octadecyl, and isomeric forms thereof. Examples of phenylsubstituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive,are (o, m, or p)-tolyl, 3,5-xylyl, (o, m, or p)-ethylphenyl,2,5-diethylphenyl, (o, m, or p)-butylphenyl, (o, m, orp)-sec-butylphenyl, (o, m, or p)-tert-butylphenyl,2-isopropyl-3-methylphenyl, 2-ethyl-4-propylphenyl,2,6-diisopropylphenyl, 3,4,5-trimethylphenyl, and 2,4,6-tributylphenyl.

When the processes of Charts A-D yield an ester, R₁₂ being methyl, thefree acid products are obtained by methods known in the art. Forexample, the PGF₂ analogs are subjected to saponification in an aqueousalkaline medium to form an alkaline salt, which is then acidified toyield the free acid. A preferred method for the PGE₂ analogs, and usefulfor the PGF₂ analogs as well, is by enzymatic hydrolysis using anesterase enzyme composition obtained from the marine invertebratePlexaura homomalla (Esper), 1792. Plexaura homomalla is a member of thesubclass Octocorallia, order Gorgonacea, suborder Holaxonia, familyPlexauridae, genus Plexaura. See, for example, Bayer, "The Shallow-WaterOctocorallia of the West Indian Region," Martinus Nijhoff, The Hague(1961). Colonies of these Plexaura homomalla are abundant on the oceanreefs in the zone from the low-tide line to about 25 fathoms in thetropical and subtropical regions of the western part of the AtlanticOcean, from Bermuda to the reefs of Brazil, including the eastern shorereefs of Florida, the Caribbean island and mainland reefs, and the Gulfof Mexico island and mainland reefs. These colonies are bush-like orsmall tree-like in habit and are readily identified for collection asPlexaura homomalla (Esper), 1792, by those of ordinary skill in thisart. Two forms exist, the R form and the S form. See W. P. Schneider etal., J. Am. Chem. Soc. 94, 2122 (1972).

The esterase enzyme composition is produced by the steps: (1) extractingcolonies or colony pieces of the marine invertebrate Plexaura homomalla(Esper), 1792, forma R or forma S, with liquid acetone for a sufficienttime to remove substantially all soluble lipids, and

(2) recovering the acetone-insoluble matter as said composition.

The colonies of Plexaura homomalla are used either in their as-harvestedform or in broken or chopped pieces. It is immaterial whether they areused fresh from their natural environment, or after freezing andthawing, or even after drying under ambient conditions.

The extraction with acetone may be done batch-wise, as by stirring in acontainer, or by percolation, or by continuous methods of extractionknown in the art. If stirring is used, it is advantageous to first chopthe Plexaura homomalla into small pieces, for example less than 3 mm. ingreatest dimension. The product is accordingly then a powder consistingof pieces smaller than 3 mm. Contact with acetone is continued untilsubstantially all of the soluble lipids are removed. Normally 1 hour issufficient, although a longer time is required for whole colonies and ashorter time is sufficient for chopped colonies with efficientextraction. The end-point can be determined simply by examination of theacetone, as by evaporation and by physical measurements on any residuethus obtained. The extraction temperature is kept below 50° C. to avoiddenaturation of the enzyme, and is preferably in the range 20° to 30° C.Lower temperatures may be used but the extraction then proceeds moreslowly. The extraction is generally done at atmospheric pressure, but itmay be carried out at higher or lower pressures provided the acetone isin a liquid state when contacting the Plexaura homomalla.

The acetone-insoluble enzyme composition is recovered from the acetoneby decantation, filtration, centrifugation, or other convenient methodfor separating solids and liquids. A small amount of adherent acetone,for example, 10% of the weight of the composition, may be left on theproduct but it is preferred that the amount be lowered to less than 1%,for example by drying under ambient conditions or under reducedpressure. The product can then be stored without deterioration,preferably at about -20° C.

in utilizing the above esterase enzyme composition for the purposes ofthis invention, the prostaglandin ester is contacted with a mixture ofthe enzyme composition and water. The ester is conveniently added as asolution, for example in ethanol or benzene, to about 50-100 times itsweight of water. The enzyme composition is added in an amount about 1-15times the weight of ester. The mixture is stirred until the ester ishydrolyzed, generally about 18-24 hours at 25° C. Temperatures of about0°-50° C. may be employed, although about 25° C. is preferred. Theprogress of hydrolysis is readily followed by analysis, for example bythin-layer chromatography by methods known in the art. See, for example,Hamberg et al., J. Biol. Chem. 241, 257 (1966). Finally, several volumesof acetone are added and the acid products dissolved in the acetone arerecovered by filtration, concentration, and extraction using methodsknown in the art.

The final formula VI-to-XVII compounds prepared by the processes of thisinvention, in free acid form, are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed above. These transformations are carriedout by a variety of procedures known in the art to be generally usefulfor the preparation of inorganic, i.e., metal or ammonium, salts, amineacid addition salts, and quaternary ammonium salts. The choice ofprocedure depends in part upon the solubility characteristics of theparticular salt to be prepared. In the case of the inorganic salts, itis usually suitable to dissolve the formula VI-to-XVII acid in watercontaining the stoichiometric amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. For example,such use of sodium hydroxide, sodium carbonate, or sodium bicarbonategives a solution of the sodium salt. Evaporation of the water oraddition of a water-miscible solvent of moderate polarity, for example,a lower alkanol or a lower alkanone, gives the solid inorganic salt ifthat form is desired.

To produce an amine salt, the formula VI-to-XVII acid is dissolved in asuitable solvent of either moderate or low polarity. Examples of theformer are ethanol, acetone, and ethyl acetate. Examples of the latterare diethyl ether and benzene. At least a stoichiometric amount of theamine corresponding to the desired cation is then added to thatsolution. If the resulting salt does not precipitate, it is usuallyobtained in solid form by addition of a miscible diluent of low polarityor by evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use stoichiometricamounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe formula VI-to-XVII acid with the stoichiometric amount of thecorresponding quaternary ammonium hydroxide in water solution, followedby evaporation of the water.

The final formula VI-to-XVII acids or esters prepared by the processesof this invention are transformed to lower alkanoates by interaction ofthe formula VI-to-XVII hydroxy compound with a carboxyacylating agent,preferably the anhydride of a lower alkanoic acid, i.e., an alkanoicacid of two to 8 carbon atoms, inclusive. For example, use of aceticanhydride gives the corresponding acetate. Similar use of propionicanhydride, isobutyric anhydride, and hexanoic acid anhydride gives thecorresponding carboxyacylates.

The carboxyacylation is advantageously carried out by mixing the hydroxycompound and the acid anhydride, preferably in the presence of atertiary amine such as pyridine or triethylamine. A substantial excessof the anhydride is used, preferably about 10 to about 10,000 moles ofanhydride per mole of the hydroxy compound reactant. The excessanhydride serves as a reaction diluent and solvent. An inert organicdiluent, for example, dioxane, can also be added. It is preferred to useenough of the tertiary amine to neutralize the carboxylic acid producedby the reaction, as well as any free carboxyl groups present in thehydroxy compound reactant.

The carboxyacylation reaction is preferably carried out in the rangeabout 0° to about 100° C. The necessary reaction time will depend onsuch factors as the reaction temperature, and the nature of theanhydride and tertiary amine reactants. With acetic anhydride, pyridine,and a 25° C. reaction temperature, a 12 to 24-hour reaction time isused.

The carboxyacylated product is isolated from the reaction mixture byconventional methods. For example, the excess anhydride is decomposedwith water, and the resulting mixture acidified and then extracted witha solvent such as diethyl ether. The desired carboxyacylate is recoveredfrom the diethyl ether extract by evaporation. The carboxyacylate isthen purified by conventional methods, advantageously by chromatography.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following preparationsand examples.

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin-Elmer model 421infrared spectrophotometer. Except when specified otherwise, undiluted(neat) samples are used.

Mass spectra are recorded on an Atlas CH--4 mass spectrometer with aTO-4 source (ionization voltage 70 ev).

NMR spectra are recorded on a Varian A-60 spectrophotometer indeuterochloroform solutions with tetramethylsilane as an internalstandard (downfield).

Brine, herein, refers to an aqueous saturated sodium chloride solution.

The A-IX solvent system used in thin layer chromatography is made upfrom ethyl acetate-acetic acid- 2,2,4-trimethylpentane-water(90:20:50:100) according to M. Hamberg and B. Samuelsson, J. Biol. Chem.241, 257 (1966).

Skellysolve-B refers to mixed isomeric hexanes.

Silica gel chromatography, as used herein, is understood to includeelution, collection of fractions, and combination of those fractionsshown by TLC (thin layer chromatography) to contain the desired productfree of starting material and impurities.

Names of compounds used in these examples are understood to refer tocompounds having the same configuration as the correspondingprostaglandins of natural configuration unless otherwise indicated inthe name. For example, the product of Example 11, 8β,12α-PGE₂, methylester, has the alpha configuration at C-11 and at C-15, but has the8-beta and 12-alpha configurations characteristic of the analogs of thisinvention.

Preparation 1 Dimethyl 2-Oxo-3-methylheptylphosphonate, ##STR97##

n-Butyllithium (150 ml.) is added slowly to a solution of dimethylmethylphosphonate (25.6 g.) in 475 ml. of tetrahydrofuran (THF) at about-65° C. To the mixture is added a solution of racemic ethyl2-methylhexanoate (18.4 g.) in 50 ml. of THF, and the resulting mixtureis stirred at -70° C. for 2 hrs. Then, 16 ml. of acetic acid is added,and the mixture is concentrated under reduced pressure. The residue ismixed with dichloromethane (about 400 ml.) and water (about 50 ml.),shaken, and separated. The organic phase is dried over magnesium sulfateand concentrated. Distillation yields the title compound, 16.7 g., b.p.126°-129° C./1 mm.

Following the procedures of Preparation 1 but replacing racemic ethyl2-methylhexanoate with the ethyl esters of the (+) and (-) isomers of2-methylhexanoic acid (see P. A. Levene et al., J. Biol. Chem. 70, 211(1926) and 84, 571 (1929)) there are obtained the correspondingoptically active (+) and (-) title compounds.

Preparation 2 Dimethyl 2-Oxo-3,3-dimethylheptylphosphonate, ##STR98##

n-Butyllithium (400 ml.) is added slowly to a solution of dimethylmethylphosphonate (73.7 g.) in 1.3 l. of THF at about -66° C. To themixture is added a solution of ethyl 2,2-dimethylhexanoate (53 g.) in150 ml. of THF, and the resulting mixture is stirred at -70° C. for 2hrs. Then, 46 ml. of acetic acid is added, and the mixture isconcentrated under reduced pressure. The residue is mixed with portionsof dichloromethane (about 1.2 l.) and water (about 150 ml.), shaken, andseparated. The organic phase is dried over magnesium sulfate andconcentrated. Distillation yields the title compound, 41.6 g., b.p.117°-120° C./1 mm.

Preparation 3 Dimethyl 2-oxo-4-phenylbutylphosphonate, ##STR99##

A solution of dimethyl methylphosphonate (115.5 g.) in 2.1 l. oftetrahydrofuran is treated, while stirring at -65° C., with a solutionof butyl lithium (660 ml. 1.6 M. in hexane). A solution of ethylhydrocinnamate (93.5 g.) in 225 ml. of tetrahydrofuran is added at -65°C. Stirring is continued at -65° C. for 2 hrs. and then at about 25° C.for 16 hrs. Acetic acid (70 ml.) is added and the mixture concentratedunder reduced pressure. The residue is partitioned betweendichloromethane and water. The organic phase is dried and concentrated.Distillation yields the title compound, b. 188°-191° C./2 mm., having amass spectral peak at 256.

Preparation 4 Aluminum Amalgam.

Granular aluminum metal (50 g.) is added to a solution of mercuricchloride (50 g.) in 2 l. of water. The mixture is swirled until hydrogengas evolution starts to become vigorous (about 30 seconds). Then, mostof the aqueous solution is decanted, and the rest is removed by rapidfiltration. The amalgamated aluminum is washed rapidly and successivelywith two 200-ml. portions of methanol and two 200-ml. portions ofanhydrous diethyl ether. The amalgamated aluminum is then covered withanhydrous diethyl ether until used.

EXAMPLE 1 3β,5β-Dihydroxy-2α-methoxymethyl-1β-cyclopentaneacetic Acidγ-Lactone (Formula XX: R₁ is methyl).

A. Refer to Chart A. The formula-XIX iodo lactone is first prepared. Forthis purpose the formula-XVIII starting material of the properconfiguration is obtained by resolution of the racemic hydroxy acid with(-)-ephedrine following the procedure of E. J. Corey et al. (J. Am.Chem. Soc. 92, 397 (1970)). The sodium salt of the laevorotatoryformula-I hydroxy acid is then treated in water at 0°-5° C. withpotassium triiodide (2.5 equivalents) for 20 hrs. to yield theformula-XIX compound, namely3β,5β-dihydroxy-4-iodo-2α-methoxymethyl-1β-cyclopentaneacetic acidγ-lactone.

B. A solution of the product of step A (20.5 g.) in 125 ml. of benzeneis treated at about 25° C. with 250 ml. of an ethereal solution (0.3 M.)of tributyltinhydride. When the reaction is complete, in approximatelyone hr. as shown by TLC (thin layer chromatography), the solution isconcentrated under reduced pressure to a liquid residue. There is added300 ml. of Skellysolve B (a mixture of isomeric hexanes) and 300 ml. ofwater, and the mixture is stirred about 16 hrs. The aqueous phase,together with washings of the organic phase, is saturated with sodiumchloride and extracted with ethyl acetate. The ethyl acetate solution isdried over sodium sulfate and concentrated to the title compound, anoil, 7.5 g; having infrared absorption at 3300, 1755, 1170, 1037, 959,and 890 cm.sup.⁻¹.

EXAMPLE 23β-p-Toluenesulfonyloxy-5β-hydroxy-2α-methoxymethyl-1β-cyclopentaneaceticAcid γ -Lactone (Formula XXI: R₁ is methyl and R₂ is p-toluenesulfonyl).

Refer to Chart A. A solution of the formula-XX compound (Example 1, 1.0g.) in 20 ml. of pyridine is stirred at about 25° C. withp-toluenesulfonyl chloride (1.9 g.) for 2 days. The mixture is dilutedwith ice, made slightly acidic with 10% sulfuric acid, and extractedwith ethyl acetate. The organic phase is washed with saturated sodiumbicarbonate solution and brine, dried over sodium sulfate, andconcentrated to the title compound, m.p. 85°-90° C., 1.8 g. Ananalytical sample has m.p. 97°-98° C., and NMR peaks at 7.80, 7.34,5.1-4.7, 3.31, 3.23, and 2.98-2.12 δ.

EXAMPLE 33α-Benzoyloxy-5β-hydroxy-2α-methoxymethyl-1β-cyclopentaneacetic Acidγ-Lactone (Formula XXII: R₁ is methyl and R₃ is benzoyl).

Refer to Chart A. A mixture of the formula-XXI compound (1.8 g.) andsodium benzoate (5.0 g.) in 100 ml. of dimethyl sulfoxide is stirred at80°-85° C. for 3.5 hrs. The mixture is then diluted with 500 ml. of icewater and extracted with diethyl ether. The organic phase is washed withsaturated sodium bicarbonate solution and brine, dried over sodiumsulfate, and concentrated to the title compound, an oil, 1.5 g; havingNMR peaks at 8.30-7.91, 7.73-7.31, 5.80-5.55, 5.34-4.98, 3.74-3.43,3.28, and 3.11-2.0 δ.

EXAMPLE 43α-Benzoyloxy-5β-hydroxy-2α-hydroxymethyl-1β-cyclopentaneacetic Acidγ-Lactone (Formula XXIII: R₃ is benzoyl).

Refer to Chart A. A solution of the formula-XXII compound (Example 3,0.5 g.) in 20 ml. of ethyl acetate is treated at 0° C., while stirring,with 0.7 ml. of boron tribromide. After 0.5 hr., stirring is continuedfor 2 hrs. at about 25° C. There is then added 75 ml. of saturatedsodium bicarbonate solution, the mixture is equilibrated, and theorganic phase is washed with brine, dried over sodium sulfate, andconcentrated to an oil, 0.47 g. The product is subjected to silica gelchromatography, eluting with 50% ethyl acetate in Skellysolve B, then75% and finally ethyl acetate. Concentration under reduced pressureyields the title compound, an oil, 0.33 g; having infrared absorption at3300, 1590, 1570, 1530, 1250, 1150, 1095, 1055, 1030, 1010, 900, 804,and 710 cm.sup.⁻¹ ; and NMR peaks at 8.17-7.83, 7.67-7.29, 5.76-5.57,5.35-4.93, 3.27, and 3.13-1.95 δ.

EXAMPLE 53α-Benzoyloxy-5β-hydroxy-2α-(3-oxo-trans-1-octenyl)-1.beta.-cyclopentaneaceticAcid γ-Lactone (Formula XXV: R₃ is benzoyl, R₄ and R₅ are hydrogen, andR₆ is n-butyl).

A. Refer to Chart A. There is first prepared the formula-XXIV aldehyde.A solution of the formula-XXIII compound (Example 4, 0.33 g.) in 2 ml.of dichloromethane is added to Collins reagent (prepared from 1.2 g. ofpyridine and 1.0 g. of anhydrous chromium trioxide in 25 ml. ofdichloromethane), with stirring at 0° C. After 5 min. at 0° C. andanother 5 min. at about 25° C., the solution is decanted from the solidsand used in step B below.

B. A solution of the appropriate ylide is prepared from a mixture ofsodium hydride (0.12 g., 50%) and dimethyl 2-oxoheptylphosphonate (0.64g.) in 22 ml. of tetrahydrofuran at 0° C. To the cold ylide solution isadded the solution of the formula-XXIV aldehyde from step A and themixture is stirred at about 25° C. for 4 hrs. The reaction mixture isadded to a mixture of 150 ml. of 2 M. sodium hydrogen sulfate, and 100ml. of diethyl ether. The organic phase is washed with saturated sodiumbicarbonate solution and brine, dried over sodium sulfate, andconcentrated to a dark liquid, 0.77 g. The residue is subjected tosilica gel chromatography, eluting with 10% and 50% ethyl acetate inSkellysolve B. Concentration under reduced pressure yields the titlecompound, 0.28 g., as an oil which slowly crystallizes. An analyticalsample, obtained by recrystallization from hexane-ethyl acetate, hasm.p. 64°-65.5° C.; mass spectral peaks at 370, 248, and 192; opticalrotation [α]_(D) -149° (in chloroform); and NMR peaks at 8.13-7.82,7.60-7.22, 7.10-6.64, 6.20, 5.75-5.50, 5.33-4.98, 4.29-3.91, and3.45-0.57 δ.

EXAMPLE 63α-Benzoyloxy-5β-hydroxy-2α-(3α-hydroxy-trans-1-octenyl)-1β-cyclopentaneaceticAcid γ-Lactone (Formula XXVI: M is ##STR100## Q is n-pentyl, and R₃ isbenzoyl) and3α-Benzoyloxy-5β-hydroxy-2α-(3β-hydroxy-trans-1-octenyl)-1β-cyclopentaneaceticAcid γ-Lactone (Formula XXVI: M is ##STR101## and Q and R₃ are asdefined above).

Refer to Chart A. A solution of the formula-XXV compound (Example 5,0.61 g.) in 40 ml. of methanol is added to a mixture of sodiumborohydride (90 mg.) in 40 ml. of methanol, with stirring at about -15°C. under nitrogen. After 1.5 hrs., 5 ml. of acetic acid is added, themixture left to warm to about 25° C., and then 5 ml. of water is added.Concentration under reduced pressure gives an oil which is dissolved inethyl acetate and equilibrated with 0.2 M. sodium hydrogen sulfate. Theorganic phase, including washings of the aqueous phase, is washed withsaturated sodium bicarbonate solution and brine, over sodium sulfate,and concentrated to an oil, 0.59 g. The residue is subjected to silicagel chromatography, eluting with 50% ethyl acetate-Skellysolve B, anddividing the eluant into 95 fractions. Fractions 48-56, when combinedand concentrated, yield the 3β-hydroxy title compound, an oil, 0.16 g.Fractions 63-95 similarly yield the 3α-hydroxy title compound, an oil,0.12 g.; having R_(f) 0.35 (TLC on silica gel in 50% ethylacetate-Skellysolve B) for the 3β-hydroxy compound, 0.30 for the3α-hydroxy compound.

EXAMPLE 73α,5β-Dihydroxy-2α-(3α-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneaceticAcid γ-Lactone (Formula XXVII: M is ##STR102## and Q is n-pentyl).

Refer to Chart A. A mixture of the 3α-hydroxyoctenyl formula-XXVIcompound (Example 6, 2.8 g.), potassium carbonate (1.4 g.), and 250 ml.of methanol is stirred for 24 hrs. at about 25° C. The solids arefiltered off and the filtrate concentrated. The residue is taken up inethyl acetate and equilibrated with brine. The organic phase is washedwith brine, dried over sodium sulfate, and concentrated to the titlecompound, 1.9 g. as an oil which slowly crystallizes. An analyticalsample, obtained by recrystallization from hexane-ethyl acetate, hasm.p. 79°-81° C.; mass spectral peaks at 250, 193, and 179; and [α]_(D)-39° (in chloroform).

Following the procedure of Example 7, but replacing the3α-hydroxyoctenyl formula-XXVI compound of that example with thecorresponding 3β-hydroxyoctenyl formula-XXVI compound (Example 6), thereis obtained3α,5β-dihydroxy-2α-(3β-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneaceticacid γ-lactone, having R_(f) 0.34 (TLC on silica gel in ethyl acetate).

EXAMPLE 83α,5β-Dihydroxy-2α-(3α-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneaceticAcid γ -Lactone, Bis(tetrahydropyranyl) Ether (Formula-XXVIII: M is##STR103## wherein THP is tetrahydropyranyl, Q is n-pentyl, and R₈ istetrahydropyranyl).

Refer to Chart B. A solution of the 3α-hydroxyoctenyl formula-XXVIIcompound (Example 7, 1.6 g.) in dihydropyran (6.2 g.), pyridinehydrochloride (0.16 g.) and 37 ml. of dichloromethane is stirred atabout 25° C. for 4 hrs. The solution is filtered through silica gel, andconcentrated under reduced pressure to an oil, 2.8 g. The oil issubjected to silica gel chromatography, yielding the title compound, anoil, 1.7 g., having R_(f) 0.63 (TLC on silica gel in 50% ethylacetate-Skellysolve B).

Following the procedure of Example 8, but replacing the3α-hydroxyoctenyl formula-XXVII compound of that example with the3β-hydroxyoctenyl formula-XXVII compound obtained following Example 7,there is obtained3α,5β-dihydroxy-2α-(3β-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneaceticacid γ-lactone, bis(tetrahydropyranyl) ether having R_(f) 0.63 (TLC) onsilica gel in 50% ethyl acetate-Skellysolve B).

EXAMPLE 93α,5β-Dihydroxy-2α-(3α-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneacetaldehydeγ-Lactol, Bis(tetrahydropyranyl) Ether (Formula XXIX: M is ##STR104## Qis n-pentyl, and R₈ is THP, wherein THP is tetrahydropyranyl, and ˜ isalpha or beta).

Refer to Chart B. A solution of the 3α-hydroxyoctenyl formula-XXVIIIcompound (Example 8, 1.7 g.) in 18 ml. of toluene is treated withstirring at -78° C. under nitrogen with 12.4 ml. of 10%diisobutylaluminum hydride in toluene. After 1 hr. there is addeddropwise to the cold mixture 24 ml. of tetrahydrofuran-water (2:1)solution. The organic phase is filtered, washed with brine, dried oversodium sulfate, and concentrated to the title compound, an oil, 1.7 g.having R_(f) 0.4 (TLC on silica gel in 50% ethyl acetate-Skellysolve B).

Following the procedure of Example 9, but replacing the3α-hydroxyoctenyl formula-XXVIII compound of that example with the3β-hydroxyoctenyl formula-XXVIII compound obtained following Example 8,there is obtained3α,5β-dihydroxy-2α-(3β-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneacetaldehydeγ-lactol, bis(tetrahydropyranyl) ether, having R_(f) 0.4 (TLC on silicagel in 50% ethyl acetate-Skellysolve B).

Example 10 8β,9β,12α-PGF₂, Methyl Ester, Bis(tetrahydropyranyl) Ether(Formula XXXII: M'" is ##STR105## Q is n-pentyl, R₉ is THP(tetrahydropyranyl), and R₁₁ is methyl).

Refer to Chart B. There is first prepared the Wittig ylide.4-Carboxybutyltriphenylphosphonium bromide (E. J. Corey et al., J. Am.Chem. Soc. 91, 5677 (1969)) (5.0 g.) is added to a solution of sodiodimethylsulfinylcarbanide prepared from sodium hydride (50%, 1.1 g.) and125 ml. of dimethylsulfoxide and the resulting solution is stirred 1.5hrs. at about 25° C.

To the above solution is added a solution of the 3α-hydroxyoctenylformula-XXIX compound (Example 9, 1.7 g.) in 50 ml. of dimethylsulfoxideand the resulting mixture is stirred at about 25° C. for 16 hrs. Themixture is then stirred with a mixture of aqueous 0.2 M. sodium hydrogensulfate at pH about 3 and diethyl ether, and the two phases separated.The organic phase is extracted with aqueous 1 N. sodium hydroxide andthen water, and the aqueous extract is acidified with aqueous 2 M.sodium hydrogen sulfate and extracted with diethyl ether. The organicextracts are washed with water and brine, dried over sodium sulfate, andconcentrated to 8β,9β,12α-PGF₂ bis(tetrahydropyranyl) ether, an oil, 1.9g. having R_(f) 0.7 (TLC, silica gel plates, in A-IX solvent system).

The methyl ester is prepared by treating the above product inether-methanol (1:1) solution at 0° C. with excess diazomethane, andconcentrating the mixture to an oil, 1.8 g. Silica gel chromatographyyields the title compound as an oil, 1.0 g., having R_(f) 0.45 (TLC onsilica fel in 50% ethyl acetate-Skellysolve B).

Following the procedure of Example 10, but replacing the3α-hydroxyoctenyl formula-XXIX compound of that example with the3β-hydroxyoctenyl formula-XXIX compound obtained following Example 9,there is obtained the corresponding C-15 epimer of the title compound,namely 8β,9β,12α,15β-PGF₂, methyl ester, bis(tetrahydropyranyl) ether,having R_(f) 0.45 (TLC on silica gel in 50% ethyl acetate-SkellysolveB).

EXAMPLE 11 8β,12α-PGE₂, Methyl Ester (Formula XXXIV: M is ##STR106## Qis n-pentyl, and R₁₂ is methyl).

Refer to Chart B. A solution of the 15α formula-XXXbis(tetrahydropyranyl) ether (Example 10, 1.0 g.) in 30 ml. ofdichloromethane is added to previously cooled (0° C.) Collins reagentprepared from pyridine (2.6 g.) and chromium trioxide (1.7 g.) in 80 ml.of dichloromethane. The mixture is stirred at about 25° C. for 10 min.and filtered. The filtrate is concentrated to an oil. A solution of theoil in diethyl ether is washed with aqueous 0.2 M. sodium hydrogensulfate, saturated aqueous sodium bicarbonate solution, and brine, driedover sodium sulfate, and concentrated to the bis(tetrahydropyranyl)ether of the title compound, an oil, 0.84 g., having R_(f) 0.5 (TLC onsilica gel in 50% ethyl acetate-Skellysolve B).

The above product is treated with 50 ml. of a solution of acetic acid,water, and tetrahydrofuran (20:10:3) at 40° C. for 3 hrs., cooled to 25°C., diluted with 70 ml. of water, and freeze-dried to the titlecompound, an oil, 0.74 g. Silica gel chromatography, taking 25 ml.fractions and eluting with 500 ml. of 20% acetone in dichloromethane,and 1000 ml. of 30% acetone in dichloromethane yields the title compoundin fractions 21-26, an oil, 0.5 g., having mass spectral peaks (for thetrimethylsilyl derivative) at 495, 492, 479, 420, and 349; and NMR peaksat 5.83-5.60, 5.50-5.20, 4.49-3.95, 3.67, and 2.98-0.67 δ.

There is also obtained, in fractions 8-10, 8β,12α-PGA₂ methyl ester, anoil, 0.06 g., having mass spectral peaks (for the trimethylsilylderivative) at 420, 405, 389, 349, and 330.

Following the procedure of Example 11, but replacing the 15α formula-XXXcompound of that example with the 15β formula-XXX compound obtainedfollowing Example 10, there is obtained 8β,12α,15β-PGE₂, methyl ester,having mass spectral peaks (for the trimethylsilyl derivative) at 510,495, 492, 439, 420, and 349; NMR peaks at 5.82-5.69, 5.52-5.24,4.49-4.00, 3.68 (singlet), and 2.75-0.73 δ: and R_(f) 0.4 (TLC on silicagel in 30% acetone-dichloromethane).

There is also obtained, as a fraction in silica gel chromatography,8β,12α,15β-PGA₂, methyl ester, having mass spectral peaks at 420, 405,389, 349, and 330, and TLC R_(f) 0.4 on silica gel in 10%acetone-dichloromethane.

EXAMPLE 12 8β,9α,12α-PGF₂, Methyl Ester (Formula XXXV: M is ##STR107## Qis n-pentyl, R₁₂ is methyl, and ˜ is alpha) and 8β,9β,12α-PGF₂, MethylEster (Formula XXXV: M is ##STR108## Q is n-pentyl, R₁₂ is methyl, and ˜is beta).

Refer to Chart B. A solution of the 15α formula-XXXIV PGE₂ analog(Example 11, 0.2 g.) in 12 ml. of methanol is added, with stirring, to aslurry of sodium borohydride (0.03 g.) in 12 ml. of methanol at -15° C.under nitrogen and stirred for one hr. There is then added 10 ml. ofacetic acid, dropwise, and the mixture is concentrated. The residue istriturated with ethyl acetate, separated, and the organic solutionconcentrated to an oil. Silica gel chromatography, eluting with 10%methanol in chloroform (saturated with boric acid) and collecting 10 ml.fractions, yields in fractions 8-11 the 9α title compound, about 0.11g.; in fractions 12-15 the 9β title compound. Further processing of the9α material by silica gel chromatography, eluting with 15-50% acetone indichloromethane yields an analytical sample of the 9α title compound, anoil, 0.06 g., having mass spectral peaks (for the trimethylsilylderivative) at 569, 553, 541, 513, 494, and 404; and NMR peaks at5.84-5.37, 4.27-3.87, 3.67 (singlet), and 2.70-0.73 δ.

Following the procedure of Example 12, but replacing the 15αformula-XXXIV PGE₂ analog of that example with the 15β formula-XXXIVcompound obtained following Example 11, there is obtained8β,9α,12α,15β-PGF₂, methyl ester, having mass spectral peaks at 584,569, 553, 541, 513, 494, and 404. Likewise there is obtained8β,9β,12α-15β-PGF₂, methyl ester, having the same properties as theproduct following Example 13.

Example 13 8β,9β,12α-PGF₂, Methyl Ester (Formula XXXI: M is ##STR109## Qis n-pentyl, and R₁₂ is methyl).

Refer to Chart B. The 15α formula-XXX bis(tetrahydropyranyl) ether(Example 10, 0.46 g.) is treated with 28 ml. of a solution of aceticacid, water, and tetrahydrofuran (20:10:3) at 40° C. for 3 hrs., cooled,and freeze-dried to the title compound, an oil, 0.34 g. Silica gelchromatography, taking 20 ml. fractions and eluting with 250 ml. of 50 %acetone in dichloromethane yields, from fractions 4-6, an analyticalsample of the title compound, an oil, 0.21 g., having mass spectralpeaks (for the trimethylsilyl derivative) at 569, 553, 541, 513, 494,and 404; and having NMR peaks at 5.75-5.30, 4.47-3.95, 3.67, and2.70-0.73 δ.

Following the procedure of Example 13, but replacing the 15α formula-XXXcompound of that example with the 15β formula-XXX compound obtainedfollowing Example 12, there is obtained 8β,9β,12α,15β-PGF₂, methylester, having mass spectral peaks at 584, 569, 553, 541, 513, 494, and404; and NMR peaks at 5.75-5.30, 4.49-3.97, 3.68 (singlet), 2.53-0.72 δ.

EXAMPLE 143β-Benzoyloxy-5β-hydroxy-2α-methoxymethyl-1β-cyclopentaneacetic Acidγ-Lactone (Formula XXXVI: R₁ is methyl and R₃ is benzoyl).

A. Refer to Charts A and C. A solution of the formula-XIX iodo lactone(Example 1A, 18 g.) in 30 ml. of pyridine at 25° C. is mixed, whilestirring, with 7.5 ml. of benzoyl chloride added dropwise and stirringis continued for 1 hr. The mixture is diluted with 60 ml. of toluene andconcentrated to an oily residue. The residue is partitioned betweenethyl acetate and 10% sulfuric acid. The organic phase is washed withsaturated sodium bicarbonate and brine, dried over sodium sulfate, andconcentrated to yield3β-benzoyloxy-5β-hydroxy-4-iodo-2α-methoxymethyl-1β-cyclopentaneaceticacid γ-lactone, 21.8 g. An analytical sample has m.p. 85°-89° C., massspectral peaks at 416, 294, 289, 262, 167, and 105, and optical rotation[α]_(D) -5° C. in chloroform.

B. A solution of the product of part A (16.8 g.) in 100 ml. of benzeneat 25° C. is mixed, with stirring, with 2.5 ml. of 0.3 M. tributyltinhydride in diethyl ether, and stirred for an additional 0.5 hr. Thesolution is concentrated to an oily residue. The residue is partitionedbetween 200 ml. of water and 200 ml. of Skellysolve B. The aqueous phaseis extracted first with Skellysolve B and then with ethyl acetate. Thecombined organic extracts are washed with brine, dried over sodiumsulfate, and concentrated to the title compound, an oil, 11.2 g., havingNMR peaks at 8.04-7.80, 7.54-7.14, 5.44-4.84, 3.35, 3.25, 3.03-1.95, and1.38-0.86 δ.

EXAMPLE 153β-Benzoyloxy-5β-hydroxy-2α-hydroxymethyl-1β-cyclopentaneacetic Acidγ-Lactone (Formula XXXVII: R₃ is benzoyl).

Refer to Chart C. A solution of boron tribromide (175 g.) in 400 ml. ofdichloromethane is added slowly to a stirred solution of theformula-XXXVI compound (Example 14, 101 g.) in 800 ml. ofdichloromethane at 0° C. After 20 hrs. The reaction is quenched bycareful addition of a solution of sodium carbonate (405 g. in 1050 ml.of water). The mixture is saturated with sodium chloride at about 25° C.and extracted with ethyl acetate. The organic phase is washed withbrine, dried over sodium sulfate, and concentrated. The residue isrecrystallized from dichloromethane-carbon tetrachloride, to yield thetitle compound, 85 g., m.p. 115°-116° C., having mass spectral peaks at276, 154, and 136, optical rotation [α]_(D) +81° in chloroform, and NMRpeaks at 8.01-7.82, 7.54-7.14, 5.54-4.89, and 3.80-2.03 δ.

EXAMPLE 16 3β-Benzoyloxy-5β-hydroxy-2α-(3-oxo-trans-1-octenyl)-1β-cyclopentaneacetic Acid γ-Lactone (Formula XXXIX: Q is n-pentyl andR₃ is benzoyl).

A. Refer to Chart C. There is first prepared the formula-XXXVIIIaldehyde. A solution of the formula-XXXVII compound (Example 15, 30.5g.) in 300 ml. of dichloromethane is added to Collins reagent (preparedfrom 107 g. of pyridine and 84 g. of anhydrous chromium trioxide in 1500ml. of dichloromethane), with stirring at 0° C. After 5 min. at 0° C.and another 5 min. at about 25° C., the solution is decanted from thesolids and used in step B below.

B. The ylide is prepared from a mixture of sodium hydride (10.6 g., 50%)and dimethyl 2-oxoheptylphosphonate (48.8 g.) in 1600 ml. oftetrahydrofuran at 0° C. To the cold ylide solution is added thesolution of the formula-XXXVIII aldehyde from step A and the mixture isstirred at about 25° C. for 4 hrs. The reaction mixture is added to amixture of 2000 ml. of 2 M. sodium hydrogen sulfate and ice, thenextracted with chloroform. The organic phase is washed with saturatedsodium bicarbonate solution and brine, dried over sodium sulfate, andconcentrated to an oily residue. The residue is taken up in diethylether and subjected to silica gel chromatography, eluting with 10% and50% ethyl acetate in Skellysolve B. Concentration under reduced pressureyields the title compound, 26.2 g., as an oil which slowly crystallizes.An analytical sample, recrystallized from hexane-ethyl acetate, has m.p.60°-62° C., and NMR peaks at 8.11-7.84, 7.62-7.20, 6.95-6.50, 6.17,5.46-4.92, 3.52, and 3.10-0.62 β.

EXAMPLE 173β-Benzoyloxy-5β-hydroxy-2α-(3α-hydroxy-trans-1-octenyl)-1β-cyclopentaneaceticAcid γ-Lactone (Formula XL: M is ##STR110## Q is n-pentyl, and R₃ isbenzoyl) and3α-Benzoyloxy-5β-hydroxy-2α-(3β-hydroxy-trans-1-octenyl)-1β-cyclopentaneaceticAcid γ-Lactone (Formula XL: M is ##STR111## and Q and R are as definedabove).

Refer to Chart C. The formula-XXXIX compound (Example 16, 33.6 g.) in250 ml. of methanol is added to a stirred mixture of sodium borohydride(5.30 g.) in 500 ml. of methanol at -20° C. under nitrogen. After 2hrs., 250 ml. of acetic acid is added slowly at -20° C., and thesolution is warmed to 25° C. and concentrated. The residue ispartitioned between ethyl acetate and 0.2 M. sulfuric acid. The organicphase is washed with saturated aqueous sodium bicarbonate and brine,dried over sodium sulfate, and concentrated to a mixture of the titlecompounds, an oil, 41.6 g. Silica gel chromatography yields the separatetitle compounds; the 3α-hydroxy compound, m.p. 76.1°-76.9° C., havingmass spectral peaks at 345, 301, and 250, and optical rotation [α]_(D)+98° (chloroform); and the 3β-hydroxy compound, m.p. 69.0-70.1° C.,having mass spectral peaks at 314, 301, and 250, and optical rotation[α]_(D) +77° (chloroform).

EXAMPLE 18 3β,5β-Dihydroxy-2α-(3α-hydroxy-trans-1-octenyl)-1β-cyclopentaneacetic Acid γ-Lactone (Formula XLI: M is ##STR112## Q isn-pentyl, and R₈ is hydrogen).

Refer to Chart C. The formula-XL compound (Example 17, 10.2 g.) isstirred with potassium carbonate (5.62 g.) in 100 ml. of methanol atabout 25° C. for 2 hrs. The mixture is filtered through silica gel andconcentrated to an oil. The oil is partitioned between brine and ethylacetate. The organic phase is dried over sodium sulfate and concentratedto a residual oil. The brine extract also yields an oil on acidification(2 M. sulfuric acid), extraction with ethyl acetate, and concentration.The combined oils are treated with pyridine hydrochloride (0.1 g.) in250 ml. of ethyl acetate at reflux for one hour, filtered, andconcentrated to the title compound, an oil, 6.9 g., having NMR peaks at5.68-5.50, 5.13-4.76, 4.25-3.80, 3.70-3.08, and 2.97-0.67 δ.

Following the procedure of Example 18 but replacing the3α-hydroxyoctenyl formula-XL compound of that example with the3β-hydroxyoctenyl compound following Example 17, there is obtained thecorresponding formula-XLI compound, namely3β,5β-dihydroxy-2α-(3β-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneaceticacid γ-lactone, having NMR peaks at 5.65-5.43, 5.07-4.74, 4.25-3.76,3.54-3.28, and 2.92-0.50 δ.

EXAMPLE 19 3β,5β-Dihydroxy-2α-(3α-hydroxy-trans-1-octenyl)-1β-cyclopentaneacetic Acid γ-Lactone, bis(tetrahydropyranyl) Ether(Formula XLI: M' is ##STR113## Q is n-pentyl, and R₈ is THP).

Refer to Chart C. A solution of the formula-XLI compound (Example 18,0.66 g.) in 20 ml. of dichloromethane, together with dihydropyran (2.5g.) and pyridine (0.075 g.) is stirred at about 25° C. for 24 hrs. Themixture is filtered through silica gel and concentrated to an oil, 1.2g. Silica gel chromatography yields the title compound, an oil, 0.67 g.,having R_(f) 0.5 (TLC on silica gel in 50% ethyl acetate-Skellysolve B).

Following the procedure of Example 19 but replacing the3α-hydroxyoctenyl formula-XLI compound with the corresponding3β-hydroxyoctenyl compound following Example 18, there is obtained3β,5β-dihydroxy-2α-(3β-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneaceticacid γ-lactone, bis(tetra-hydropyranyl) ether, having R_(f) 0.5 (TLC onsilica gel in 50% ethyl acetate-Skellysolve B).

EXAMPLE 203β,5β-Dihydroxy-2α-(3α-hydroxy-trans-1-octenyl)-1.beta.-cyclopentaneaceticAcid γ-Lactol, Bis(tetrahydropyranyl), Ether (Formula XLII: M' is##STR114## Q is n-pentyl, and R₈ is THP).

Refer to Chart C. A solution of the formula-XLI compound (Example 19,0.67 g.) in 20 ml. of toluene is treated, while stirring at -78° C.under nitrogen, with 5 ml. of 10% diisobutylaluminum hydride in toluene.After one hr. there is slowly added to the cold mixture 24 ml. oftetrahydrofuran-water (2:1) solution. The organic phase is filtered,washed with brine, dried over sodium sulfate, and concentrated to thetitle compound, an oil, 0.67 g., having TLC R_(f) 0.3 on silica gel in50% ethyl acetate-Skellysolve B.

Following the procedure of Example 20 but replacing the3α-hydroxyoctenyl formula-XLI compound of that example with thecorresponding 3β-hydroxyoctenyl compound following Example 19 there isobtained3β,5β-dihydroxy--(:(3β-hydroxy-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactol, bis(tetrahydropyranyl) ether, an oil, having R_(f) 0.3(TLC on silica gel in 50% ethyl acetate-Skellysolve B).

EXAMPLE 21 8β,9β,11β,12α-PGF₂, Methyl Ester, Bis(tetra-hydropyranyl)Ether (Formula XLIII: M' is ##STR115## Q is n-pentyl, R₁₀ is THP, andR₁₂ is methyl).

Refer to Chart C. Following the procedure of Example 10, the Wittigylide prepared from 4-carboxybutyltriphenylphosphonium bromide isreacted with the 3α-hydroxyoctenyl formula-XLII compound (Example 20,10.7 g.). Thereafter, following the procedure of Example 10, the titlecompound is obtained, an oil, 0.55 g., having R_(f) 0.6 (TLC on silicagel in 50% ethyl acetate-Skellysolve B).

Likewise following the procedure of Example 10, but employing the3β-hydroxyoctenyl formula-XLII compound following Example 20 (18.2 g.),there is obtained the corresponding C-15 epimer of the title compound,namely 8β,9β,11β,12α,15β-PGF₂, methyl ester, bis(tetrahydropyranyl)ether, an oil, 12.5 g., having R_(f) 0.5 (TLC on silica gel in 50% ethylacetate-Skellysolve B).

EXAMPLE 22 8β,11β,12α-PGE₂, Methyl Ester (Formula XLVI: M'" is##STR116## Q is n-pentyl, R₈ is hydrogen, and R₁₂ is methyl).

Refer to Chart C. Following the procedures of Example 11, the 15αformula-XLIII PGF₂ -type compound (Example 21, 0.55 g.) is treated withCollins reagent to yield the corresponding bis(tetrahydropyranyl) etherof the title compound, an oil, 0.50 g., having R_(f) 0.6 (TLC on silicagel in 50% ethyl acetate-Skellysolve B).

Following the procedures of Example 11, the above product is treatedwith acetic acid-water-tetrahydrofuran to yield the title compound, anoil, 0.17 g. having mass spectral peaks at 495, 479, 439, 420, and 349;NMR peaks at 5.77-5.60, 5.50-5.26, 4.32-3.87, 3.67 (singlet), and 3.05-0.61 δ; and optical rotation [α]_(D) +67° (in tetrahydrofuran).

As in Example 11, there is also obtained the PGA₂ analog, namely8β,12α,15α-PGA₂ methyl ester.

Likewise following the procedures of Example 11, but employing the 15βformula-XLIII PGF₂ -type compound (Example 21, 12.5 g.) there areobtained the corresponding C-15 epimers of the above compounds, namely:8β,11β,12α,15β-PGE₂, methyl ester, bis(tetrahydropyranyl) ether, havingR_(f) 0.6 (TLC on silica gel in 50% ethyl acetate-Skellysolve B).8β,11β,12α,15β-PGE₂, methyl ester, having mass spectral peaks at 495,492, 439, 420, and 349, NMR peaks at 5.72- 5.37, 4.32-3.83, 3.68(singlet), and 2.75-0.69 δ, and optical rotation [α]_(D) +55° (intetrahydrofuran); and 8β,12α,15β-PGA₂, methyl ester.

EXAMPLE 23 8β,9α,11β,12α-PGF₂, Methyl Ester (Formula LIV: M is##STR117## Q is n-pentyl, R₁₂ is methyl, and ˜ is alpha) and8β,9β,11β,12α-PGF₂, Methyl Ester (Formula LIV: M is ##STR118## Q isn-pentyl, R₁₂ is methyl, and ˜ is beta).

Refer to Chart D. Following the procedures of Example 12, the 15αformula-LIII 8β,11β,12α-PGE₂, methyl ester (Example 22, 0.12 g.) isreduced with sodium borohydride, yielding the title compounds. The 9αtitle compound is the more polar material, an oil, 0.021 g., having massspectral peaks at 569, 553, 541, 513, and 494. The 9β title compound isan oil, having mass spectral peaks at 569, 553, 541, 513, and 494; NMRpeaks at 6.10-5.32, 4.32-3.81, 3.67 (singlet), and 2.60-0.76 δ; andoptical rotation [α]_(D) -9° (in tetrahydrofuran).

Likewise following the procedures of Example 12, but employing the 15βformula-LIII compound, namely 8β,11β,12α, -15β-PGE₂, methyl ester(Example 22, 1.0 g.) the corresponding C-15 epimers of the abovecompounds are obtained, namely: 8β,9α,11β,12α,15β-PGF₂, methyl ester,m.p. 90°-91° C., having mass spectral peaks at 569, 553, 541, 503, 494,479, 463, and 457; NMR peaks at 5.64-5.34, 4.17-3.78, 3.67 (singlet),and 3.00-0.45 δ; and optical rotation [α]_(D) +7° (in ethanol); and8β,9β,11β,12α,15β-PGF₂, methyl ester, identical with the 15β product ofExample 24.

Example 24 8β,9β,11β,12α-PGF₂, Methyl Ester (Formula LIV: M is##STR119## Q is n-pentyl, R₁₂ is methyl, and ˜ is beta).

Following the procedure of Example 12, the 15α formula-XLIII8β,9β,11β,12α-PGF₂, methyl ester, bis(tetrahydropyranyl) ether (Example21, 0.11 g.) is treated in acetic acid-water-tetrahydrofuran to yieldthe title compound having the same properties as the 15α product ofExample 23.

Likewise following the procedure of Example 13, but employing the 15βformula-XLIII compound, namely 8β,9β,11β,-12α,15β-PGF₂, methyl ester,bis(tetrahydropyranyl) ether following Example 21, there is obtained thecorresponding C-15 epimer of the title compound, namely 8β,9β,11β,12α,15β-PGF₂, methyl ester, an oil, having mass spectral peaks at 569, 553,541, 513, 423, and 404. NMR peaks at 5.64-5.26, 4.27-3.77, 3.67(singlet), 3.34-2.86, and 2.53-0.67 δ; and optical rotation [α]_(D) -24°(in ethanol).

EXAMPLE 253β-Benzoyloxy-5β-hydroxy-2α-(3-methyl-trans-1-octenyl)-1.beta.-cyclopentaneaceticAcid γ- Lactone (Formula XL: M is ##STR120## Q is n-pentyl, and R₃ isbenzoyl).

Refer to Chart C. A solution of the formula-XXXIX compound (Example 16,0.20 g.) in 15 ml. of tetrahydrofuran is treated, while stirring at -78°C., with methyl magnesium bromide (3 M. solution in diethyl ether) addeddropwise. After 2 hrs. stirring, 10 ml. of saturated aqueous ammoniumchloride is added dropwise and the mixture is warmed to 25° C. Themixture is diluted with diethyl ether and water, equilibrated, andseparated. The organic phase is washed with brine, dried over sodiumsulfate, and concentrated to the title compounds, on oil.

EXAMPLE 263β,5β-Dihydroxy-2α-(3-methyl-trans-1-octenyl)-1β-cyclopentaneacetic Acidγ-Lactone (Formula XLI: M' is ##STR121## Q is n-pentyl, and R₈ ishydrogen).

Refer to Chart C. A solution of the formula-XL compounds (Example 25,0.50 g.) in 10 ml. of methanol is treated, while stirring at about 25°C. under nitrogen, with 1.0 ml. of a 25% solution of sodium methoxide inmethanol. After 20 min., 2 ml. of acetic acid is added, and the mixtureis concentrated under reduced pressure to an oil. The residue isdissolved in ethyl acetate and extracted with saturated aqueous sodiumbicarbonate. The organic phase is washed with brine, dried over sodiumsulfate, and concentrated to the title compounds, a yellow oil.

EXAMPLE 273β,5β-Dihydroxy-2α-(3-methyl-trans-1-octenyl)-1β-cyclopentaneacetic Acidγ-Lactol (Formula XLII: M' is ##STR122## Q is n-pentyl, and R₈ ishydrogen).

Refer to Chart C. A solution of the formula-XLI compounds (Example 26,0.50 g.) in 15 ml. of tetrahydrofuran is treated, while stirring at -78°C. under nitrogen, with 12 ml. of 12% diisobutylaluminum hydride intoluene. Saturated aqueous ammonium chloride (15 ml.) is added. Thereaction mixture is warmed to 25° C., shaken with ethyl acetate andwater, and filtered. The filtrate is equilibrated with brine and ethylacetate. The organic phase is washed with brine, dried over sodiumsulfate, and concentrated to the title compounds, an oil.

EXAMPLE 28 Mixed 15-Epimers of 15-Methyl-8β,9β,11β,12α-PGF₂, MethylEster (Formula XLIII: M'" Is ##STR123## Q is n-pentyl, R₁₀ is hydrogen,and R₁₂ is methyl).

Refer to Chart C. The formula-XLII compounds (Example 27, 0.51 g. areadded to a Wittig reagent prepared from 4-carboxybutyltriphenylphosphonium bromide (2.4 g.) and sodiodimethylsulfinylcarbanide (from 0.52 g. of 50% sodium hydride and 15 ml.of dimethylsulfoxide). The reaction mixture is stirred at about 25° C.for 16 hrs., and then added to a mixture of 0.2 M. sodium bisulfate inice water and diethyl ether, whereby the resulting pH is about 1.0.After equilibration, the aqueous phase is extracted with diethyl ether.The organic extracts are combined, washed with 1 N. sodium hydroxide andwater. The aqueous washings are combined and acidified to pH less than3.0 with 2 M. sodium bisulfate. The mixture is extracted with diethylether, and the organic phase is washed with water, dried over sodiumsulfate, and concentrated to the free acids corresponding to the titlecompounds (wherein R₁₂ is hydrogen), an oil.

The above product is dissolved in ether, dichloromethane, and methanol,and treated with excess ethereal diazomethane to give the titlecompounds, an oil.

EXAMPLE 29 15-Methyl-8β,9β,11β,12α-PGF₂, Methyl Ester (Formula-XLIV: M'"is ##STR124## CL Q is n-pentyl, R₉ is hydrogen, and R₁₁ is methyl) andits C-15 epimer, 15-Methyl-8β,9β,11β ,12α,15β-PGF₂, Methyl Ester.

The formula-XLIII mixed C-15 epimers of Example 28 are subjected tosilica gel chromatography, eluting with 30% acetone in dichloromethane.The less polar compound is the 15α isomer, obtained by combining theearly (less polar) fractions. The 15β title compound is obtained bycombining the later fractions.

The 15α isomer has mass spectral peaks at 583, 527, 508, 437, and 418;NMR peaks at 5.7-5.2, 4.35-3.80, 3.70 (singlet), 1.28 (singlet), and2.6-0.7 δ; optical rotation [α]_(D) -29° (in ethanol).

The 15β isomer has mass spectral peaks at 583, 528, 508, 437, and 418;NMR peaks at 5.7-5.2, 4.35-3.80, 3.70 (singlet), 1.28 (singlet), and2.6-0.7 δ; optical rotation [α]_(D) -25° (in ethanol).

EXAMPLE 30 15-Methyl-8β,11β,12α-PGE₂, Methyl Ester (Formula-XLVI: M'" is##STR125## Q is n-pentyl, R₉ is hydrogen, and R₁₁ is methyl).

A. Refer to Chart C. The formula-XLIV 15-methyl-8β ,9β,11β,12α-PGF₂,methyl ester, 11-trimethylsilyl ether is first prepared. A solution ofthe formula-XLIV 15-methyl-8β,9β,11β,12α-PGF₂, methyl ester (Example 29,0.50 g.) in 20 ml. of acetone is treated, while stirring at -45° C.under nitrogen, dropwise with 2.0 ml. of N-trimethylsilyl-diethylamine.After one hour at -45° C., the solution is diluted with 80 ml. ofdiethyl ether and partitioned with 5% aqueous sodium bicarbonate. Theorganic phase is washed with brine, dried over sodium sulfate, andconcentrated to the 11-trimethylsilyl ether.

B. The product of step A (0.61 g.) in 15 ml. of dichloromethane is addedto Collins reagent at 0° C. (previously prepared from 1.0 g. of chromiumtrioxide, 1.6 g. pyridine, and 50 ml. of dichloromethane). The mixtureis stirred for 10 min., then decanted and filtered. The filtrate isconcentrated under reduced pressure to the formula-XLV15-methyl-8β,11β,12α-PGE₂, methyl ester, 11-trimethylsilyl ether.

C. The product of step B (0.57 g.) in 30 ml. of methanol is treated,while stirring at about 25° C., with a solution of 1.5 ml. of aceticacid in 15 ml. of water. After the mixture is homogeneous, it ispartitioned between diethyl ether and 0.2 M. sodium hydrogen sulfate.The organic phase is washed with saturated aqueous sodium bicarbonateand brine, dried over sodium sulfate, and concentrated. The residue issubjected to silica gel chromatography to obtained the title compound,having mass spectral peaks at 519, 493, 453, 434, 363, and 344; NMRpeaks at 5.7-5.2, 4.4-3.8, 3.68 (singlet), 1.28 (singlet) and 3.0- 0.7δ; and optical rotation [α]_(D) +78° (in chloroform).

Following the procedures of Example 30, but replacing the formula-XLIV15-methyl-8β,9β,11β,12α-PGF₂, methyl ester with the formula-XLIV15-methyl-8β,9β,11β,12α,15β-PGF₂, methyl ester (Example 29), there areobtained, respectively:

15-methyl-8β,9β,11β,12α,15β-PGF₂, methyl ester, 11-trimethylsilyl ether,

15-methyl-8β,11β,12α,15β-PGE₂, methyl ester, 11-trimethylsilyl ether,and

15-methyl-8β,11β,12α,15 β-PGE₂, methyl ester.

The last-named compound has a mass spectral peak at 524.3326 for thesilylated derivative; NMR peaks at 5.7-5.2, 4.4-3.8, 3.67 (singlet),1.29 (singlet), and 3.0-0.7 δ; and optical rotation [α]_(D) +77° (inchloroform).

EXAMPLE 31 15-Methyl-8β,9α,11β,12 α-PGF₂, Methyl Ester. (Formula-LIV: Mis ##STR126## Q is n-pentyl, R₁₂ is methyl, and ˜ is alpha).

Refer to Chart D. The formula-LIII 15-methyl-8β,11β,12 α-PGE₂, methylester (Example 30, 0.12 g.) is added to a stirred mixture of sodiumborohydride (0.018 g.) in 6 ml. of methanol at -20° C. under nitrogen.After 30 min., 6 ml. of acetic acid is added, the mixture is warmed toabout 25° C., and concentrated. The residue is dissolved in ethylacetate and washed with 0.2 M. sulfuric acid. The organic phase iswashed with saturated aqueous sodium bicarbonate and brine, dried oversodium sulfate, and concentrated. The mixed C-9 epimers are separated bysilica gel chromatography, the less polar material being15-methyl-8β,9β,11β,12 α-PGF₂, methyl ester; the more polar materialbeing the title compound (43% yield) having R_(f) 0.13 (TLC on silicagel in 30% acetone in dichloromethane) and mass spectral peaks (for thetrimethylsilyl derivative) at 583, 567, 527, 508, 493, 486, and 217.

Following the procedures of Example 31 but replacing the formula-LIII15-methyl-8β,11β,12 α-PGE₂, methyl ester with the formula-LIII15-methyl-8β,11β,12α,15 β-PGE₂, methyl ester following Example 30, thereare obtained 15-methyl-8β,9β,11β,12α,15 β-PGF₂, methyl ester, and15-methyl-8β,9α,11β,12α,15 β-PGF₂, methyl ester.

EXAMPLE 32 15-Methyl-8β,12 α-PGA₂, Methyl Ester (Formula XLVII: M' is##STR127## Q is n-pentyl, and R₁₂ is methyl).

A. Refer to Chart C. There is first prepared 15-methyl-8β,11β,12 α-PGE₂,11-acetate, methyl ester. A solution of the formula-XLVI15-methyl-8β,11β,12 α-PGE₂, methyl ester (Example 30, 0.52 g.) in 52 ml.of pyridine is treated, while stirring at about 25° C. under nitrogen,with 5.4 ml. of acetic anhydride. After 5 hrs. stirring, the mixture isadded to 500 ml. of 2 M. sodium hydrogen sulfate, ice, and ethylacetate, and equilibrated. The organic phase is washed with saturatedaqueous sodium bicarbonate and brine, dried over sodium sulfate, andconcentrated to an oil, 0.68 g., having R_(f) 0.34 (TLC on silica gel in5% acetone-dichloromethane).

B. The 11-acetate from step A (0.68 g.) is stirred with potassiumacetate (1.2 g.) in 45 ml. of methanol at about 25° C. After 18 hrs. themixture is added to a mixture of saturated aqueous sodium bicarbonateand ethyl acetate, and equilibrated. The organic phase is washed withbrine, dried over sodium sulfate, and concentrated to the titlecompound, an oil, 0.51 g., having R_(f) 0.41 (TLC on silica gel in 5%acetone-dichloromethane); and NMR peaks at 7.6-7.4, 6.25-6.05, 5.6-5.3,3.67 (singlet), 3.4-3.1, 1.27 (singlet), and 2.7-0.7 δ.

EXAMPLE 33 15-Methyl-8β,12 α-PGA₂, 10,11-Epoxide, Methyl Ester (FormulaXLVIII: M'" is ##STR128## Q is n-pentyl, and R₂₀ is methyl).

Refer to Chart D. The formula-XLVII compound (Example 32, 0.18 g.) in 5ml. of methanol is treated, while stirring at -25° C. under nitrogen,with a solution of 0.7 ml. of 30% aqueous hydrogen peroxide and 0.35 ml.of 1 N. sodium hydroxide. After 1 hour, there is added 2 N. hydrochloricacid dropwise to pH 5- 6. The mixture is diluted with brine andextracted with diethyl ether. The organic phase is washed with saturatedaqueous sodium bicarbonate and brine, dried over sodium sulfate, andconcentrated to the title compound, an oil.

EXAMPLE 34 15-Methyl-8β,12 α-PGE₂, Methyl Ester (Formula L: M is##STR129## Q is n-pentyl, and R₁₂ is methyl) and 15-Methyl-8β,11β,12α-PGE₂, Methyl Ester (Formula L: M is ##STR130## Q is n-pentyl, ˜ isbeta, and R₁₂ is methyl).

Refer to Chart D. A mixture of the formula-XLVIII 15-methyl-8β,12α-PGA₂, 10,11-epoxide, methyl ester (Example 33, 0.20 g.), aluminumamalgam (Preparation 4, 0.16 g.), 8 ml. of diethyl ether, 1.6 ml. ofmethanol, and 4 drops of water is stirred at about 25° C. for 48 hrs.The mixture is filtered and the filtrate is concentrated to the mixedtitle compounds, an oil, 0.17 g. Separation by silica gel chromatographyeluting with ethyl acetate-Skellysolve B yields the 11α compound as theless polar compound, and the 11β compound as the more polar compound.The 11α isomer has NMR peaks at 5.8-5.6, 5.5-5.2, 4.5-4.2, 3.67(singlet), 1.30 (singlet), 3.0-0.7 δ.

EXAMPLE 35 15-Methyl-8β,12α,15 β-PGE₂, Methyl Ester (Formula LI: M is##STR131## Q is n-pentyl, and R₁₂ is methyl) and 15-Methyl-8β,11β,12α,15β-PGE₂, Methyl Ester) Formula LIII: M is ##STR132## Q is n-pentyl, andR₁₂ is methyl).

Refer to Charts C and D. Following the procedures of Example 32 butreplacing the formula-XLVI 15-methyl-8β,11β,12 α-PGE₂, methyl ester ofthat example with the formula-XLVI 15-methyl-8β,11β,12α,15β -PGE₂,methyl ester following Example 30, there are obtained, respectively15-methyl-8β,11β,12α,15β -PGE₂, 11-acetate, methyl ester and15-methyl-8β,12α,15 β-PGA₂, methyl ester.

Following the procedure of Example 33 but employing the above PGA₂analog, there is obtained the formula-XLVIII 15-methyl-8β,12α,15 β-PGA₂,10,11-epoxide, methyl ester.

Finally, following the procedure of Example 34, the above PGA₂ epoxideanalog is transformed to the title compounds. The formula-LI (11α)compound (obtained in 23% yield) has R_(f) 0.5 (TLC on silica gel in 30%acetone in dichloromethane; mass spectral peaks (for the trimethylsilylderivative) at 537, 535, 493, 453, 434, 419, 363, 344, and 309; and NMRpeaks at 5.84-5.60, 5.48-5.24, 4.50-4.24, 4.50-4.25, 3.68 (singlet) and3.20-0.67 δ.

EXAMPLE 36 15-Methyl-8β,9α,12 α-PGF₂, Methyl Ester (Formula LII: M is##STR133## Q is n-pentyl, and R₁₂ is methyl) and 15-Methyl-8β,9β,12α-PGF₂, Methyl ester (Formula LII: M is ##STR134## Q is n-pentyl, andR₁₂ is methyl).

Refer to Chart D. Following the procedures of Example 12, but replacingthe 15α formula-XXXIV PGE₂ analog of that example with the formula-LI15-methyl-8β,12 α-PGE₂, methyl ester of Example 34, yields after silicagel chromatography the title compounds. The 9α compound (obtained in 39%yield) has R_(f) 0.3 (TLC on boric acid-impregnated silica gel inchloroform-methanol-acetic acid (95-5- 1); mass spectral peaks (for thetrimethylsilyl derivative) at 508, 455, 418, and 217; and NMR peaks at5.82-5.35, 4.26-3.77, 3.68 (singlet), and 3.17-0.68. The 9β compound(obtained in 4% yield) has R_(f) 0.1 (TLC on boric acid-impregnatedsilica gel in chloroform-methanol-acetic acid (95-5- 1)) and massspectral peaks at 583, 567, 527, and 508.

Likewise following the procedures of Example 12 but employing theformula-LI 15-methyl-8β,12α,15 β-PGE₂, methyl ester of Example 35, thereare obtained 15-methyl-8β,9α,12α,15 β-PGF₂, methyl ester, and15-methyl-8β,9β,12α,15β -PGF₂, methyl ester. The 9α compound (obtainedin 68% yield) has R_(f) 0.3 (TLC on boric acid-impregnated silica gel inchloroform-methanol-acetic acid (95-5- 1); mass spectral peaks (for thetrimethylsilyl derivative) at 583, 527, 508, 455, and 418; infraredabsorption at 3400, 2950, 1740, 1413, 1210, 1083, 976, and 758 cm.sup.⁻¹; and NMR peaks at 5.80-5.10, 4.14- 3.80, 3.68 (singlet), 3.16(singlet), and 2.57-0.62 δ.

EXAMPLE 37 16-Methyl-8β,12 α-PGE₂, Methyl Ester (Formula XXXIV: M is##STR135## Q is --CH(CH₃)--(CH₂)₃ --CH₃, and R₁₂ is methyl).

Refer to Charts A and B. Following the procedures of Examples 5 and 6,but replacing the ylide of Example 5 with the ylide prepared fromdimethyl 2-oxo-3-methylheptylphosphonate (Preparation 1), there areobtained the corresponding formula-XXV compounds,3α-benzoyloxy-5β-hydroxy-2α-(3α-hydroxy-4-methyl-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactone and3α-benzoyloxy-5β-hydroxy-2α-(3β-hydroxy-4-methyl-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactone.

Thereafter, following the procedures of Examples 7-11, inclusive, theabove 3α-hydroxy-4-methyloctenyl intermediates are transformed to theabove title compounds.

Likewise following the procedures of Example 7-11, inclusive, butemploying the 3β-hydroxy-4-methyloctenyl intermediates above, there areobtained the corresponding C-15 epimers, namely 16-methyl-8β,12α,15β-PGE₂, methyl ester.

EXAMPLE 38 16-Methyl-8β,9α,12 α -PGF₂, Methyl Ester (Formula XXXV: M is##STR136## Q is --CH(CH₃)--(CH₂)₃ --CH₃, and R₁₂ is methyl) and16-Methyl-8β,9β,12 α-PGF₂, Methyl Ester (Formula XXXV: M is ##STR137## Qis --CH(CH₃)--(CH₂)₃ --CH₃, and R₁₂ is methyl).

Refer to Chart B. Following the procedures of Example 12, but replacingthe 15α formula-XXXIV PGE₂ analog of that example with the product ofExample 37, namely 16-methyl-8β,12 α-PGE₂, methyl ester, the above titlecompounds are obtained.

Likewise following the procedures of Example 12, but employing the 15βanalog, namely 16-methyl-8β,12α,15 β-PGE₂, methyl ester obtainedfollowing Example 37, there are obtained the corresponding C-15 epimers,namely 16-methyl-8β,9α,12α,15 β-PGF₂, methyl ester, and16-methyl-8β,9β,12α,15β -PGF₂, methyl ester.

EXAMPLE 39 16-Methyl-8β,11β,12 α-PGE₂, Methyl Ester (Formula XLVI: M'"is ##STR138## Q is CH(CH₃)--(CH₂)₃ --CH₃ , R₈ is hydrogen, and R₁₂ ismethyl).

Refer to Charts A and C. Following the procedures of Example 16 and 17,but replacing the ylide of Example 16 with the ylide prepared fromdimethyl 2-oxo-3-methylheptylphosphonate (Preparation 1), there areobtained the corresponding formula-XL compounds,3β-benzoyloxy-5β-hydroxy-2α-(3α-hydroxy-4-methyl-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactone and3β-benzoyloxy-5β-hydroxy-2α-(3β-hydroxy-4-methyl-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactone.

Thereafter, following the procedures of Examples 18-22, inclusive, theabove 3α-hydroxy-4-methyloctenyl intermediates are transformed to theabove title compounds.

Likewise following the procedures of Examples 18-22, inclusive, butemploying the 3β-hydroxy-4-methyloctenyl intermediates above, there areobtained the corresponding C-15 epimers, namely 16-methyl-8β ,11β ,12α,15β -PGE₂, methyl ester.

EXAMPLE 40 16-Methyl-8β,9α,11β ,12α-PGF₂, Methyl Ester (Formula LIV: Mis ##STR139## Q is --CH(CH₃)--(CH₂)₃ --CH₃, and R₁₂ is methyl) and16-Methyl-8β,9β,11β,12 α-PGF₂, Methyl Ester (Formula LIV: M is##STR140## Q is --CH(CH₃)--(CH₂)₃ --CH₃, and R₁₂ is methyl).

Refer to Chart D. Following the procedures of Example 12, the 15αformula-LIII 16-methyl-8β,11β,12 α-PGE₂, methyl ester of Example 39 isreduced with sodium borohydride to the title compounds, which areseparated by silica gel chromatrography.

Likewise following the procedures of Example 12, but employing the 15βformula-LIII 16-methyl-8β,11β,12α,15 β-PGE₂, methyl ester followingExample 39, there are obtained the corresponding C-15 epimers, namely16-methyl-8β,9α,11β,12α,15 β-PGF₂, methyl ester, and16-methyl-8β,9β,11β,12α,15 β -PGF₂, methyl ester.

EXAMPLE 41 16,16-Dimethyl-8β,12 α-PGE₂, Methyl Ester (Formula XXXIV: Mis ##STR141## Q is --CH(CH₃)₂ --(CH₂)₃ --CH₃, and R₁₂ is methyl).

Refer to Charts A and B. Following the procedures of Examples 5 and 6,but replacing the ylide of Example 5 with the ylide prepared fromdimethyl 2-oxo-3,3-dimethylheptylphosphonate (Preparation 2), there areobtained the corresponding formula-XXV compounds,3α-benzoyloxy-5β-hydroxy-2α-(3α-hydroxy-4,4-dimethyl-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactone and3α-benzoyloxy-5β-hydroxy-2α-(3β-hydroxy-4,4-dimethyl-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactone.

Thereafter, following the procedures of Examples 7-11, inclusive, theabove 3α-hydroxy-4,4-dimethyloctenyl) intermediate is transformed to theabove title compound (42% yield) having R_(f) 0.5 in ethyl acetate; massspectral peaks (for the trimethylsilyl derivative) at 583, 523, 507,439, 349, and 295; and NMR peaks at 5.88- 5.19, 4.50-4.29, 3.98-3.85,3.67 (singlet), 3.10-2.85, 2.70-0.70, 1.25 (singlet) and 0.88 (singlet)δ.

Likewise following the procedures of Examples 7-11, inclusive, butemploying the 3β-hydroxy-4,4-dimethyloctenyl intermediate above, thereis obtained the corresponding C-15 epimer, namely16,16-dimethyl-8β,12α,15 β-PGE₂, methyl ester (56% yield) having R_(f)0.4 in ethyl acetate; mass spectral peaks (for the trimethylsilylderivative) at 537, 523, 507, 439, 349, and 295; and NMR peaks at5.87-5.70, 5.53-5.24, 4.48-4.28, 3.98-3.77, 3.67 (single), 3.30-0.71,1.25 (singlet) and 0.90 (singlet) δ.

EXAMPLE 43 16,16-Dimethyl-8β,9α,12 α-PGF₂, Methyl Ester (Formula XXXV: Mis ##STR142## Q is --C(CH₃)₂ --(CH₂)₃ --CH₃, and R₁₂ is methyl) and16,16-Dimethyl-8β,9β,12 α-PGF₂, Methyl Ester (Formula XXXV: M is##STR143## Q is --C(CH₃)₂ --(CH₂)₃ --CH₃, and R₁₂ is methyl).

Refer to Chart B. Following the procedures of Example 12, but replacingthe 15α formula-XXXIV PGE₂ analog of that example with the product ofExample 41, namely 16,16-dimethyl-8β,12 α-PGE₂, methyl ester, the abovetitle compounds are obtained. The 9α compound (obtained in 62% yield)has R_(f) 0.3 (TLC on silica gel in ethyl acetate); mass spectral peaks(for the trimethylsilyl derivative) at 611, 597, 581, 555, 522, 513,507, 491, 423, 397, 333, 307, and 217; and NMR peaks at 5.86- 5.30,4.24-3.75, 3.67 (singlet), 3.17 (singlet), 2.50-0.37, 1.25 (singlet),and 0.90 (singlet). Following the procedures of Example 13, the 9βcompound is obtained in 69% yield, having R_(f) 0.3 (TLC on silica gelin ethyl acetate); mass spectral peaks (for trimethylsilyl derivative)at 597, 581, 522, 513, 423, 397, 333, 307, and 217; and NMR peaks at5.50-5.26, 4.47-3.77, 3.67 (singlet), 2.71-0.63, 1.25 (singlet) and 0.88(singlet) δ.

Likewise following the procedures of Example 12, but employing the 15βanalog, namely 16,16-dimethyl-8β,12α,15 β-PGE₂, methyl ester, obtainedfollowing Example 41, there are obtained the corresponding C-15 epimers,namely 16,16-dimethyl-8β,9α,12α,15 β-PGF₂, methyl ester, and16,16-dimethyl-8β,9β,12α,15 β-PGF₂, methyl ester. The 9α compound(obtained in 73% yield) has R_(f) 0.2 (TLC on silica gel in ethylacetate); mass spectral peaks (for the trimethylsilyl derivative) at611, 597, 581, 555, 522, 513, 507, 491, 423, 397, 333, 307, and 217; andNMR peaks at 611, 597, 581, 555, 522, 513, 507, 491, 423, 397, 333, 307,and 217 δ. Following the procedure of Example 13, the 9β compound isobtained in 91% yield, having m.p. 41°-42.8° C. (from diethylether-hexane); R_(f) 0.2 (TLC on silica gel in ethyl acetate); massspectral peaks (for trimethylsilyl derivative) 597, 581, 555, 522, 513,423, 397, 333, 307, and 217; and NMR peaks at 5.50-5.27, 4.52-3.57, 3.67(singlet), 3.01-0.63, 1.25 (singlet), and 0.90 (singlet) δ.

EXAMPLE 43 16,16-Dimethyl-8β,11β ,12α-PGE₂, Methyl Ester (Formula XLVI:M'" is ##STR144## Q is --C(CH₃)₂ --(CH₂)₃ --CH₃, R₈ is hydrogen, and R₁₂is methyl).

Refer to Charts A and C. Following the procedures of Examples 16 and 17,but replacing the ylide of Example 16 with the ylide prepared fromdimethyl 2-oxo-3,3-dimethylheptylphosphonate (Preparation 2), there areobtained the corresponding formula-XL compounds,3β-benzoyloxy-5β-hydroxy-2α-(3α-hydroxy-4,4-dimethyl-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactone and3β-benzoyloxy-5β-hydroxy-2α-(3β-hydroxy-4,4-dimethyl-trans-1-octenyl)-1β-cyclopentaneaceticacid γ-lactone.

Thereafter, following the procedures of Examples 18-22, inclusive, theabove 3α-hydroxy-4,4-dimethyloctenyl intermediate is transformed to theabove title compound.

Likewise following the procedures of Examples 18-22, inclusive, butemploying the 3β-hydroxy-4,4-dimethyloctenyl intermediate above, thereis obtained the corresponding C-15 epimer, namely16,16-dimethyl-8β,11β,12α,15β-PGE₂, methyl ester.

EXAMPLE 44 16,16-Dimethyl-8β,9α,11β,12α-PGF₂, Methyl Ester (FormulaXXXV: M is ##STR145## Q is --C(CH₃)₂ --(CH₂)₃ --CH₃, and R₁₂ is methyl)and 16,16-Dimethyl-8β,9β,11β,12α-PGF₂, Methyl Ester (Formula XXXV: M is##STR146## Q is --C(CH₃)₂ --(CH₂)₃ --CH₃, and R₁₂ is methyl).

Refer to Chart B. Following the procedures of Example 12, but replacingthe 15α formula-XXXIV PGE₂ analog of that example with the product ofExample 43, namely 16,16-dimethyl-8β,11β,12α-PGE₂, methyl ester, theabove title compounds are obtained.

Likewise following the procedures of Example 12, but employing the 15βanalog, namely 16,16-dimethyl-8β,11β,12α,-15β-PGE₂, methyl ester,obtained following Example 43, there are obtained the corresponding C-15epimers, namely 16,16-dimethyl-8β,9α,11β,12α,15β-PGF₂, methyl ester, and16,16-dimethyl-8β,9β,11β,12α,15β-PGF₂, methyl ester.

EXAMPLE 45 17-Phenyl-18,19,20-trinor-8β,12α-PGE₂, Methyl Ester (FormulaXXXIV: M is ##STR147## Q is ##STR148## and R₁₂ is methyl).

Refer to Charts A and B. Following the procedures of Examples 5 and 6,but replacing the ylide of Example 5 with the ylide prepared fromdimethyl 2-oxo-4-phenylbutylphosphonate (Preparation 3), there areobtained the corresponding formula-XXV compounds,3α-benzoyloxy-5β-hydroxy-2α-(3α-hydroxy-5-phenyl-trans-1-pentenyl)-1β-cyclopentaneaceticacid γ-lactone and3α-benzoyloxy-5β-hydroxy-2α-(3β-hydroxy-5-phenyl-trans-1-pentenyl)-1β-cyclopentaneaceticacid γ-lactone.

Thereafter, following the procedure of Examples 7-11, inclusive, theabove 3α-hydroxy-5-phenylpentenyl intermediate is transformed to theabove title compound (76% yield) having R_(f) 0.5 (TLC on silica gel inethyl acetate) and NMR peaks at 7.20 (singlet), 5.87-5.67, 5.48-5.20,4.47-3.90, 3.63 (singlet), and 3.58-1.05 δ.

Likewise following the procedures of Examples 7-11, inclusive, butemploying the 3β-hydroxy-5-phenylpentenyl intermediate above, there isobtained the corresponding C-15 epimer, namely17-phenyl-18,19,20-trinor-8β,12α,15β-PGE₂ methyl ester.

EXAMPLE 46 17-Phenyl-18,19,20-trinor-8β,9α,12α-PGF₂, Methyl Ester(Formula XXXV: M is ##STR149## Q is ##STR150## R₁₂ is methyl) and17-Phenyl-18,19,20-trinor-8β,9β,12α-PGF₂, Methyl Ester (Formula XXXV: Mis ##STR151## Q is ##STR152## R₁₂ is methyl).

Refer to Chart B. Following the procedures of Example 12, but replacingthe 15α formula-XXXIV PGE₂ analog of that example with the product ofExample 45, namely 17-phenyl-18,19,20-trinor-8β,12α-PGE₂, methyl ester,the above title compounds are obtained. The 9α compound (obtained in 62%yield) has R_(f) 0.5 (TLC on silica gel in ethyl acetate) and NMR peaksat 7.2 (singlet), 5.87-5.67, 5.48-5.20, 4.47-3.90, 3.63 (singlet), and3.58-1.05 δ. The 9β compound (obtained in 14% yield by the procedures ofExample 12 and 93% yield by the procedures of Example 13) has R_(f) 0.3(TLC on silica gel in 30% acetone in dichloromethane) and NMR peaks at7.23 (singlet), 5.80-5.23, 4.48-3.82, 3.65 (singlet), and 3.02-0.80 δ.

Likewise following the procedures of Example 12, but employing the 15βanalog, namely 17-phenyl-18,19,20-trinor-8β,12α,15β-PGE₂, methyl ester,obtained following Example 45, there are obtained the corresponding C-9epimers, namely 17-phenyl-18,19,20-trinor-8β,9α,12α,15β-PGF₂, methylester, and 17-phenyl-18,19,20-trinor-8β,9β,12α,15β-PGF₂, methyl ester.

EXAMPLE 47 17-Phenyl-18,19,20-trinor-8β,11β,12α-PGE₂, Methyl Ester(Formula XLVI:M'" is ##STR153## Q is ##STR154## R₈ is hydrogen, and R₁₂is methyl).

Refer to Charts A and C. Following the procedures of Examples 16 and 17,but replacing the ylide of Example 16 with the ylide prepared fromdimethyl 2-oxo-4-phenylbutylphosphonate (Preparation 3), there areobtained the corresponding formula-XL compounds,3β-benzoyloxy-5β-hydroxy-2α-(3α-hydroxy-5-phenyl-trans-1-pentenyl)-1β-cyclopentaneaceticacid γ-lactone and3β-benzoyloxy-5β-hydroxy-2α-(3β-hydroxy-5-phenyl-trans-1-pentenyl)-1β-cyclopentaneaceticacid γ-lactone.

Thereafter, following the procedures of Examples 18-22, inclusive, theabove 3α-hydroxy-5-phenylpentenyl intermediate is transformed to theabove title compound.

Likewise following the procedures of Examples 18-22, inclusive, butemploying the 3β-hydroxy-5-phenylpentenyl intermediate above, there isobtained the corresponding C-15 epimer, namely17-phenyl-18,19,20-trinor-8β,11β,12α,-15β-PGE.sub. 2, methyl ester.

EXAMPLE 48 17-Phenyl-18,19,20-trinor-8β,9α,11β,12α-PGF₂, Methyl Ester(Formula XXXV: M is ##STR155## Q is ##STR156## and R₁₂ is methyl) and17-Phenyl-18,19,20-trinor-8β,9β,12α-PGF₂, Methyl Ester (Formula XXXV: Mis ##STR157## Q is ##STR158## and R₁₂ is methyl).

Refer to Chart B. Following the procedures of Example 12, but replacingthe 15α formula-XXXIV PGE₂ analog of that example with the product ofExample 47, namely 17-phenyl-18,19,20-trinor-8β,11β,12α-PGE₂, methylester, the above title compounds are obtained.

Likewise following the procedures of Example 12, but employing the 15βanalog, namely 17-phenyl-18,19,20-trinor-,11β,12α,15β-PGE₂, methylester, obtained following Example 47, there are obtained thecorresponding C-9 epimers, namely17-phenyl-18,19,20-trinor-8β,9α,11β,12α,15 β-PGF₂, methyl ester, and17-phenyl-18,19,20-trinor-8β,9β,11β,12α,15β-PGF.sub.2, methyl ester.

EXAMPLE 493α-Benzoyloxy-5β-hydroxy-2α-(3α-methoxy-trans-1-octenyl)-1β-cyclopentaneaceticAcid γ-Lactone (Formula LVI: M'v is ##STR159## Q is n-pentyl, and R₃ isbenzoyl)

Refer to Chart E. A mixture of the formula-XXVI alpha hydroxy compound(Example 6, 2.0 g.), silver oxide (4.0 g.), and 50 ml. of methyl iodideis stirred and heated at reflux for 68 hr. The mixture is cooled andfiltered, and the filtrate concentrated. The residue is subjected tosilica gel chromatography to obtain the formula-LVI title compound.

Following the procedure of Example 49, but replacing the methyl iodideof that example with other alkyl halides, there are obtained thecorresponding formula-LVI alkyl esters. Thus, with methyl bromide, ethylchloride, isopropyl iodide, butyl bromide, or pentyl iodide, there areobtained the formula-LVI compound in which R₂₂ is methyl, ethyl,isopropyl, n-butyl or n-pentyl.

EXAMPLE 50 8β,9β,12α-PGF₂, Methyl Ester, 15-Methyl Ether (Formula LXI:M'v is ##STR160## Q is n-pentyl, and R₁₂ is methyl); and 8β,12α-PGE₂,Methyl Ester, 15-Methyl Ether (Formula LXIV: M^(1v) is ##STR161## Q isn-pentyl, and R₁₂ is methyl).

Refer to Chart E. Following the procedures of Example 7, 8, 9, 10, and11, but starting with the formula-LVI 3α-methoxyoctenyl compound ofExample 49, there are obtained the corresponding intermediates andproducts as follows:

3α,5β-dihydroxy-2α-methoxy-trans-1-octenyl)-1β-cyclopentaneacetic acidγ-lactone (formula LVII) and its tetrahydropyranyl ether (formulaLVIII);

3α,5β-dihydroxy-2α-(3α-methoxy-trans-1-octenyl)-1.beta.-cyclopentaneacetaldehydeγ-lactol, tetrahydropyranyl ether (formula LIX;

8β,9β,12α-pgf₂, methyl ester, 11-tetrahydropyranyl ether, 15-methylether (formula LX);

8β,12α-pge₂, methyl ester, 11-tetrahydropyranyl ether, 15-methyl ether(formula LXIII);

and the title compounds.

EXAMPLE 51 15-Methyl-8β,11β,12α-PGE₂ (Formula LIII: M is ##STR162## Q isn-pentyl, and R₁₂ is hydrogen).

There is first prepared an esterase composition from Plexaura homomalla,which see W. P. Schneider et al., J. Am. Chem. Soc. 94, 2122 (1972).Freshly harvested colony pieces of Plexaura homomalla (Esper), 1792,forma S (10 kg.), are chopped into pieces less than 3 mm. in theirlongest dimension, and then covered with about three volumes (20 l.) ofacetone. The mixture is stirred at about 25° C. for about 1 hour. Thesolids are separated by filtration, washed with 1-2 liters of acetone,air dried, and finally stored at about -20° C. as a coarse enzymaticpowder.

A suspension of the above powder (2.5 g.) in 25 ml. of water is combinedwith a solution of 15-methyl-8β,11β,-12α-PGE₂, methyl ester (Example 30,0.5 g.) in about 0.8 ml. of ethanol previously acidified to pH 6 withphosphoric acid. The mixture is stirred at about 25° C. for 24 hrs.Then, 50 ml. of acetone is added, the mixture is stirred briefly andfiltered, and the filtrate is concentrated under reduced pressure. Theaqueous residue is acidified to pH 3.5 with citric acid and extractedwith dichloromethane. The combined extracts are concentrated underreduced pressure to the title compound.

Following the procedure of Example 51, but replacing the methyl ester ofthat example with the methyl esters of and following Examples 11, 12,and 13 there are obtained the corresponding free acids, namely

8β,12α-PGE₂

8β,12α,15β-pge₂

8β,12α-pga₂

8β,12α,15β-pga₂

8β,9α,12α-pgf₂

8β,9α,12α,15β-pgf₂

8β,9β,12α-pgf₂ and

8β,9β,12α,15β-PGF₂

Likewise, applying the procedure of Example 51 to the methyl esters ofand following Examples 22, 23, 24, 29, 30, 31, and 34-50, inclusive,there are obtained the corresponding free acids.

EXAMPLE 52 8β,12α-PGE₂, Ethyl Ester.

A solution of diazoethane (about 0.5 g.) in 25 ml. of diethyl ether (25ml.) is added to a solution of 8β,12α-PGE₂ (following Example 51, 50mg.) in 25 ml. of a mixture of methanol and diethyl ether (1:1). Themixture is allowed to stand at 25° C. for 5 min. Then, the mixture isconcentrated to give the title compound.

Following the procedure of Example 52, each of the other 8β,12α-PGE₂ or-PGF₂ type free acids defined above is converted to the correspondingethyl ester.

Also following the procedure of Example 52, but using in place of thediazoethane, diazobutane, 1-diazo-2-ethylhexane, and diazocyclohexane,there are obtained the corresponding butyl, 2-ethylhexyl, and cyclohexylesters of 8β,12α,15α-PGE₂. In the same manner, each of the other8β,12α-PGE₂ or -PGF₂ type free acids defined above is converted to thecorresponding butyl, 2-ethylhexyl, and cyclohexyl esters.

EXAMPLE 53 8β,12α-PGE₂, Methyl Ester, Diacetate.

Acetic anhydride (5 ml.) and pyridine (5 ml.) are mixed with8β,12α-PGE₂, methyl ester (following Example 51, 20 mg.), and themixture is allowed to stand at 25° C. for 18 hrs. The mixture is thencooled to 0° C., diluted with 50 ml. of water, and acidified with 5%hydrochloric acid to pH 1. That mixture is extracted with ethyl acetate.The extract is washed successively with 5% hydrochloric acid, 5% aqueoussodium bicarbonate solution, water, and brine, dried and concentrated togive the title compound.

Following the procedure of Example 53, but replacing the aceticanhydride with propionic anhydride, isobutyric anhydride, and hexanoicacid anhydride, there are obtained the corresponding dipropionate,diisobutyrate and dihexanoate derivatives of 8β,12α-PGE₂, methyl ester.

Also following the procedure of Example 53, but replacing the8β,12α-PGE₂ compound with 8β,9α,12α-PGF₂ and 8β,9β,12α-PGF₂ there areobtained the corresponding triacetate derivatives of the 8β,12α-PGF₂compounds.

Also following the procedure of Example 53, each of the 8β,12α-PGE₂ or-PGF₂ type esters and free acids defined above is transformed to thecorresponding acetates, propionates, isobutyrates, and hexanoates, thePGE-type derivatives being dicarboxyacylates, and the PGF-typederivatives being tricarboxyacylates.

EXAMPLE 54 8β,12α-PGE₂ Sodium Salt.

A solution of 8β,12α-PGE₂ (following Example 51, 100 mg.) in 50 ml. of awater-ethanol mixture (1:1) is cooled to 5° C. and neutralized with anequivalent amount of 0.1 N aqueous sodium hydroxide solution. Theneutral solution is evaporated to give the title compound.

Following the procedure of Example 54 but using potassium hydroxide,calcium hydroxide, tetramethylammonium hydroxide, andbenzyltrimethylammonium hydroxide in place of sodium hydroxide, thereare obtained the corresponding salts of 8β,12α-PGE₂.

Also following the procedure of Example 54 each of the 8β,12α-PGE-typeor-PGF-type acids defined above is transformed to the sodium, potassium,calcium, tetramethylammonium, and benzyltrimethylammonium salts.

I claim:
 1. An optically active compound of the formula ##EQU1## whereinR₄, R₅, and R₇ are hydrogen or methyl, being the same or different; withthe proviso that at least one of R₄ and R₅ is methyl; andwherein R₁₃ ishydrogen, alkyl of one to 10 carbon atoms, inclusive, cycloalkyl of 3 to10 carbon atoms, inclusive, aralkyl of 10 to 12 carbon atoms, inclusive,phenyl, or phenyl substituted with one, 2, or 3 chloro or alkyl of oneto 4 carbon atoms, inclusive; including the lower alkanoates thereof,and the pharmacologically, acceptable salts thereof wherein R₁₃ ishydrogen.
 2. A compound according to claim 1, wherein R₄ and R₅ aremethyl.
 3. 16,16-Dimethyl-8β,11β,12α-PGF₂ .sub.α, a compound accordingto claim
 2. 4. 16,16-Dimethyl-8β,11β,12α-PGF₂ .sub.α, methyl ester acompound according to claim
 2. 5. An optically active compound of theformula ##EQU2## wherein R₁₃ is hydrogen, alkyl of one to 10 carbonatoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkylof 10 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted withone, 2, or 3 chloro or alkyl of one to 4 carbon atoms,inclusive;including the lower alkanoates thereof, and thepharmacologically acceptable salts thereof wherein R₁₃ is hydrogen;wherein R₂₂ is alkyl of one to 4 carbon atoms, inclusive; including thelower alkanoates thereof, and the pharmacologically acceptable saltsthereof wherein R₁₃ is hydrogen.